Sodium Channels: Ion channels that specifically allow the passage of SODIUM ions. A variety of specific sodium channel subtypes are involved in serving specialized functions such as neuronal signaling, CARDIAC MUSCLE contraction, and KIDNEY function.Sodium Channel Blockers: A class of drugs that act by inhibition of sodium influx through cell membranes. Blockade of sodium channels slows the rate and amplitude of initial rapid depolarization, reduces cell excitability, and reduces conduction velocity.Ion Channels: Gated, ion-selective glycoproteins that traverse membranes. The stimulus for ION CHANNEL GATING can be due to a variety of stimuli such as LIGANDS, a TRANSMEMBRANE POTENTIAL DIFFERENCE, mechanical deformation or through INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS.Sodium: A member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23.NAV1.8 Voltage-Gated Sodium Channel: A voltage-gated sodium channel subtype that is expressed in nociceptors, including spinal and trigeminal sensory neurons. It plays a role in the transmission of pain signals induced by cold, heat, and mechanical stimuli.Epithelial Sodium Channels: Sodium channels found on salt-reabsorbing EPITHELIAL CELLS that line the distal NEPHRON; the distal COLON; SALIVARY DUCTS; SWEAT GLANDS; and the LUNG. They are AMILORIDE-sensitive and play a critical role in the control of sodium balance, BLOOD VOLUME, and BLOOD PRESSURE.NAV1.2 Voltage-Gated Sodium Channel: A voltage-gated sodium channel subtype that mediates the sodium ion permeability of excitable membranes. Defects in the SCN2A gene which codes for the alpha subunit of this sodium channel are associated with benign familial infantile seizures type 3, and early infantile epileptic encephalopathy type 11.NAV1.5 Voltage-Gated Sodium Channel: A voltage-gated sodium channel subtype that mediates the sodium ion PERMEABILITY of CARDIOMYOCYTES. Defects in the SCN5A gene, which codes for the alpha subunit of this sodium channel, are associated with a variety of CARDIAC DISEASES that result from loss of sodium channel function.NAV1.7 Voltage-Gated Sodium Channel: A voltage-gated sodium channel subtype found widely expressed in nociceptive primary sensory neurons. Defects in the SCN9A gene, which codes for the alpha subunit of this sodium channel, are associated with several pain sensation-related disorders.Ion Channel Gating: The opening and closing of ion channels due to a stimulus. The stimulus can be a change in membrane potential (voltage-gated), drugs or chemical transmitters (ligand-gated), or a mechanical deformation. Gating is thought to involve conformational changes of the ion channel which alters selective permeability.NAV1.6 Voltage-Gated Sodium Channel: A voltage-gated sodium channel subtype found widely expressed in neurons of the central and peripheral nervous systems. Defects in the SCN8A gene which codes for the alpha subunit of this sodium channel are associated with ATAXIA and cognitive deficits.Calcium Channels: Voltage-dependent cell membrane glycoproteins selectively permeable to calcium ions. They are categorized as L-, T-, N-, P-, Q-, and R-types based on the activation and inactivation kinetics, ion specificity, and sensitivity to drugs and toxins. The L- and T-types are present throughout the cardiovascular and central nervous systems and the N-, P-, Q-, & R-types are located in neuronal tissue.Voltage-Gated Sodium Channels: A family of membrane proteins that selectively conduct SODIUM ions due to changes in the TRANSMEMBRANE POTENTIAL DIFFERENCE. They typically have a multimeric structure with a core alpha subunit that defines the sodium channel subtype and several beta subunits that modulate sodium channel activity.NAV1.1 Voltage-Gated Sodium Channel: A voltage-gated sodium channel subtype that is predominantly expressed in the CENTRAL NERVOUS SYSTEM. Defects in the SCN1A gene which codes for the alpha subunit of this sodium channel are associated with DRAVET SYNDROME, generalized epilepsy with febrile seizures plus, type 2 (GEFS+2), and familial hemiplegic migraine type 3.NAV1.3 Voltage-Gated Sodium Channel: A voltage-gated sodium channel subtype found in neuronal tissue that mediates the sodium ion PERMEABILITY of excitable membranes.NAV1.4 Voltage-Gated Sodium Channel: A voltage-gated sodium channel subtype that mediates the sodium ion PERMEABILITY of SKELETAL MYOCYTES. Defects in the SCN4A gene, which codes for the alpha subunit of this sodium channel, are associated with several MYOTONIC DISORDERS.Sensitivity and Specificity: Binary classification measures to assess test results. Sensitivity or recall rate is the proportion of true positives. Specificity is the probability of correctly determining the absence of a condition. (From Last, Dictionary of Epidemiology, 2d ed)Membrane Potentials: The voltage differences across a membrane. For cellular membranes they are computed by subtracting the voltage measured outside the membrane from the voltage measured inside the membrane. They result from differences of inside versus outside concentration of potassium, sodium, chloride, and other ions across cells' or ORGANELLES membranes. For excitable cells, the resting membrane potentials range between -30 and -100 millivolts. Physical, chemical, or electrical stimuli can make a membrane potential more negative (hyperpolarization), or less negative (depolarization).NAV1.9 Voltage-Gated Sodium Channel: A voltage-gated sodium channel subtype found in the neurons of the NERVOUS SYSTEM and DORSAL ROOT GANGLIA. It may play a role in the generation of heat and mechanical pain hypersensitivity.Sodium Channel Agonists: A class of drugs that stimulate sodium influx through cell membrane channels.Electrophysiology: The study of the generation and behavior of electrical charges in living organisms particularly the nervous system and the effects of electricity on living organisms.Tetrodotoxin: An aminoperhydroquinazoline poison found mainly in the liver and ovaries of fishes in the order TETRAODONTIFORMES, which are eaten. The toxin causes paresthesia and paralysis through interference with neuromuscular conduction.Saxitoxin: A compound that contains a reduced purine ring system but is not biosynthetically related to the purine alkaloids. It is a poison found in certain edible mollusks at certain times; elaborated by GONYAULAX and consumed by mollusks, fishes, etc. without ill effects. It is neurotoxic and causes RESPIRATORY PARALYSIS and other effects in MAMMALS, known as paralytic SHELLFISH poisoning.Patch-Clamp Techniques: An electrophysiologic technique for studying cells, cell membranes, and occasionally isolated organelles. All patch-clamp methods rely on a very high-resistance seal between a micropipette and a membrane; the seal is usually attained by gentle suction. The four most common variants include on-cell patch, inside-out patch, outside-out patch, and whole-cell clamp. Patch-clamp methods are commonly used to voltage clamp, that is control the voltage across the membrane and measure current flow, but current-clamp methods, in which the current is controlled and the voltage is measured, are also used.Potassium Channels, Inwardly Rectifying: Potassium channels where the flow of K+ ions into the cell is greater than the outward flow.Batrachotoxins: Batrachotoxin is the 20-alpha-bromobenzoate of batrachotoxin A; they are toxins from the venom of a small Colombian frog, Phyllobates aurotaenia, cause release of acetylcholine, destruction of synaptic vesicles and depolarization of nerve and muscle fibers.Calcium Channel Blockers: A class of drugs that act by selective inhibition of calcium influx through cellular membranes.Potassium Channel Blockers: A class of drugs that act by inhibition of potassium efflux through cell membranes. Blockade of potassium channels prolongs the duration of ACTION POTENTIALS. They are used as ANTI-ARRHYTHMIA AGENTS and VASODILATOR AGENTS.Voltage-Gated Sodium Channel Blockers: A class of drugs that inhibit the activation of VOLTAGE-GATED SODIUM CHANNELS.Electric Conductivity: The ability of a substrate to allow the passage of ELECTRONS.Chloride Channels: Cell membrane glycoproteins that form channels to selectively pass chloride ions. Nonselective blockers include FENAMATES; ETHACRYNIC ACID; and TAMOXIFEN.Oocytes: Female germ cells derived from OOGONIA and termed OOCYTES when they enter MEIOSIS. The primary oocytes begin meiosis but are arrested at the diplotene state until OVULATION at PUBERTY to give rise to haploid secondary oocytes or ova (OVUM).Potassium Channels, Voltage-Gated: Potassium channel whose permeability to ions is extremely sensitive to the transmembrane potential difference. The opening of these channels is induced by the membrane depolarization of the ACTION POTENTIAL.Drug Resistance: Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from DRUG TOLERANCE which is the progressive diminution of the susceptibility of a human or animal to the effects of a drug, as a result of continued administration.Scorpion Venoms: Venoms from animals of the order Scorpionida of the class Arachnida. They contain neuro- and hemotoxins, enzymes, and various other factors that may release acetylcholine and catecholamines from nerve endings. Of the several protein toxins that have been characterized, most are immunogenic.Xenopus laevis: The commonest and widest ranging species of the clawed "frog" (Xenopus) in Africa. This species is used extensively in research. There is now a significant population in California derived from escaped laboratory animals.Kinetics: The rate dynamics in chemical or physical systems.Action Potentials: Abrupt changes in the membrane potential that sweep along the CELL MEMBRANE of excitable cells in response to excitation stimuli.Calcium Channels, L-Type: Long-lasting voltage-gated CALCIUM CHANNELS found in both excitable and nonexcitable tissue. They are responsible for normal myocardial and vascular smooth muscle contractility. Five subunits (alpha-1, alpha-2, beta, gamma, and delta) make up the L-type channel. The alpha-1 subunit is the binding site for calcium-based antagonists. Dihydropyridine-based calcium antagonists are used as markers for these binding sites.Veratridine: A benzoate-cevane found in VERATRUM and Schoenocaulon. It activates SODIUM CHANNELS to stay open longer than normal.Molecular Sequence Data: Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.Potassium: An element in the alkali group of metals with an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte that plays a significant role in the regulation of fluid volume and maintenance of the WATER-ELECTROLYTE BALANCE.Voltage-Gated Sodium Channel beta-1 Subunit: A voltage-gated sodium channel beta subunit abundantly expressed in SKELETAL MUSCLE; HEART; and BRAIN. It non-covalently associates with voltage-gated alpha subunits. Defects in the SCN1B gene, which codes for this beta subunit, are associated with generalized epilepsy with febrile seizures plus, type 1, and Brugada syndrome 5.Drug Screening Assays, Antitumor: Methods of investigating the effectiveness of anticancer cytotoxic drugs and biologic inhibitors. These include in vitro cell-kill models and cytostatic dye exclusion tests as well as in vivo measurement of tumor growth parameters in laboratory animals.Mutation: Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.Xenopus: An aquatic genus of the family, Pipidae, occurring in Africa and distinguished by having black horny claws on three inner hind toes.Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION.Shaker Superfamily of Potassium Channels: Voltage-gated potassium channels whose primary subunits contain six transmembrane segments and form tetramers to create a pore with a voltage sensor. They are related to their founding member, shaker protein, Drosophila.Dose-Response Relationship, Drug: The relationship between the dose of an administered drug and the response of the organism to the drug.Epithelial Sodium Channel Blockers: A subclass of sodium channel blockers that are specific for EPITHELIAL SODIUM CHANNELS.KATP Channels: Heteromultimers of Kir6 channels (the pore portion) and sulfonylurea receptor (the regulatory portion) which affect function of the HEART; PANCREATIC BETA CELLS; and KIDNEY COLLECTING DUCTS. KATP channel blockers include GLIBENCLAMIDE and mitiglinide whereas openers include CROMAKALIM and minoxidil sulfate.Potassium Channels, Calcium-Activated: Potassium channels whose activation is dependent on intracellular calcium concentrations.Lidocaine: A local anesthetic and cardiac depressant used as an antiarrhythmia agent. Its actions are more intense and its effects more prolonged than those of PROCAINE but its duration of action is shorter than that of BUPIVACAINE or PRILOCAINE.Amiloride: A pyrazine compound inhibiting SODIUM reabsorption through SODIUM CHANNELS in renal EPITHELIAL CELLS. This inhibition creates a negative potential in the luminal membranes of principal cells, located in the distal convoluted tubule and collecting duct. Negative potential reduces secretion of potassium and hydrogen ions. Amiloride is used in conjunction with DIURETICS to spare POTASSIUM loss. (From Gilman et al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed, p705)Drug Resistance, Neoplasm: Resistance or diminished response of a neoplasm to an antineoplastic agent in humans, animals, or cell or tissue cultures.Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the NERVOUS SYSTEM.Voltage-Gated Sodium Channel beta-3 Subunit: A voltage-gated sodium channel beta subunit subtype that non-covalently associates with voltage-gated alpha subunits. Defects in the SCN3B gene which codes for this beta subunit are associated with Brugada syndrome 7.Ranvier's Nodes: Regularly spaced gaps in the myelin sheaths of peripheral axons. Ranvier's nodes allow saltatory conduction, that is, jumping of impulses from node to node, which is faster and more energetically favorable than continuous conduction.Cell Line: Established cell cultures that have the potential to propagate indefinitely.Time Factors: Elements of limited time intervals, contributing to particular results or situations.Large-Conductance Calcium-Activated Potassium Channels: A major class of calcium activated potassium channels whose members are voltage-dependent. MaxiK channels are activated by either membrane depolarization or an increase in intracellular Ca(2+). They are key regulators of calcium and electrical signaling in a variety of tissues.Antineoplastic Agents: Substances that inhibit or prevent the proliferation of NEOPLASMS.Parasitic Sensitivity Tests: Tests that demonstrate the relative effectiveness of chemotherapeutic agents against specific parasites.Acid Sensing Ion Channels: A family of proton-gated sodium channels that are primarily expressed in neuronal tissue. They are AMILORIDE-sensitive and are implicated in the signaling of a variety of neurological stimuli, most notably that of pain in response to acidic conditions.Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes.Cells, Cultured: Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.Cyclic Nucleotide-Gated Cation Channels: A subgroup of cyclic nucleotide-regulated ION CHANNELS within the superfamily of pore-loop cation channels. They are expressed in OLFACTORY NERVE cilia and in PHOTORECEPTOR CELLS and some PLANTS.Ganglia, Spinal: Sensory ganglia located on the dorsal spinal roots within the vertebral column. The spinal ganglion cells are pseudounipolar. The single primary branch bifurcates sending a peripheral process to carry sensory information from the periphery and a central branch which relays that information to the spinal cord or brain.Calcium Channels, N-Type: CALCIUM CHANNELS that are concentrated in neural tissue. Omega toxins inhibit the actions of these channels by altering their voltage dependence.Kv1.2 Potassium Channel: A delayed rectifier subtype of shaker potassium channels that is selectively inhibited by a variety of SCORPION VENOMS.Calcium Channels, T-Type: A heterogenous group of transient or low voltage activated type CALCIUM CHANNELS. They are found in cardiac myocyte membranes, the sinoatrial node, Purkinje cells of the heart and the central nervous system.Voltage-Gated Sodium Channel beta-2 Subunit: A voltage-gated sodium channel beta subunit that binds covalently to voltage-gated alpha subunits.Rats, Sprague-Dawley: A strain of albino rat used widely for experimental purposes because of its calmness and ease of handling. It was developed by the Sprague-Dawley Animal Company.Pyrethrins: The active insecticidal constituent of CHRYSANTHEMUM CINERARIIFOLIUM flowers. Pyrethrin I is the pyretholone ester of chrysanthemummonocarboxylic acid and pyrethrin II is the pyretholone ester of chrysanthemumdicarboxylic acid monomethyl ester.Cell Membrane: The lipid- and protein-containing, selectively permeable membrane that surrounds the cytoplasm in prokaryotic and eukaryotic cells.Models, Biological: Theoretical representations that simulate the behavior or activity of biological processes or diseases. For disease models in living animals, DISEASE MODELS, ANIMAL is available. Biological models include the use of mathematical equations, computers, and other electronic equipment.Mexiletine: Antiarrhythmic agent pharmacologically similar to LIDOCAINE. It may have some anticonvulsant properties.Voltage-Gated Sodium Channel beta-4 Subunit: A voltage-gated sodium channel beta subunit subtype that covalently associates with voltage-gated alpha subunits. Defects in the SCN4B gene, which codes for this beta subunit, are associated with long QT syndrome-10.Degenerin Sodium Channels: A family of mechanosensitive sodium channels found primarily in NEMATODES where they play a role in CELLULAR MECHANOTRANSDUCTION. Degenerin sodium channels are structurally-related to EPITHELIAL SODIUM CHANNELS and are named after the fact that loss of their activity results in cellular degeneration.Nerve Tissue ProteinsInhibitory Concentration 50: The concentration of a compound needed to reduce population growth of organisms, including eukaryotic cells, by 50% in vitro. Though often expressed to denote in vitro antibacterial activity, it is also used as a benchmark for cytotoxicity to eukaryotic cells in culture.Conotoxins: Peptide neurotoxins from the marine fish-hunting snails of the genus CONUS. They contain 13 to 29 amino acids which are strongly basic and are highly cross-linked by disulfide bonds. There are three types of conotoxins, omega-, alpha-, and mu-. OMEGA-CONOTOXINS inhibit voltage-activated entry of calcium into the presynaptic membrane and therefore the release of ACETYLCHOLINE. Alpha-conotoxins inhibit the postsynaptic acetylcholine receptor. Mu-conotoxins prevent the generation of muscle action potentials. (From Concise Encyclopedia Biochemistry and Molecular Biology, 3rd ed)Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body.Decapodiformes: A superorder of CEPHALOPODS comprised of squid, cuttlefish, and their relatives. Their distinguishing feature is the modification of their fourth pair of arms into tentacles, resulting in 10 limbs.TRPC Cation Channels: A subgroup of TRP cation channels that contain 3-4 ANKYRIN REPEAT DOMAINS and a conserved C-terminal domain. Members are highly expressed in the CENTRAL NERVOUS SYSTEM. Selectivity for calcium over sodium ranges from 0.5 to 10.Protein Structure, Tertiary: The level of protein structure in which combinations of secondary protein structures (alpha helices, beta sheets, loop regions, and motifs) pack together to form folded shapes called domains. Disulfide bridges between cysteines in two different parts of the polypeptide chain along with other interactions between the chains play a role in the formation and stabilization of tertiary structure. Small proteins usually consist of only one domain but larger proteins may contain a number of domains connected by segments of polypeptide chain which lack regular secondary structure.Ether-A-Go-Go Potassium Channels: A family of voltage-gated potassium channels that are characterized by long N-terminal and C-terminal intracellular tails. They are named from the Drosophila protein whose mutation causes abnormal leg shaking under ether anesthesia. Their activation kinetics are dependent on extracellular MAGNESIUM and PROTON concentration.Protein Subunits: Single chains of amino acids that are the units of multimeric PROTEINS. Multimeric proteins can be composed of identical or non-identical subunits. One or more monomeric subunits may compose a protomer which itself is a subunit structure of a larger assembly.Cockroaches: Insects of the order Dictyoptera comprising several families including Blaberidae, BLATTELLIDAE, Blattidae (containing the American cockroach PERIPLANETA americana), Cryptocercidae, and Polyphagidae.Erythromelalgia: A peripheral arterial disease that is characterized by the triad of ERYTHEMA, burning PAIN, and increased SKIN TEMPERATURE of the extremities (or red, painful extremities). Erythromelalgia may be classified as primary or idiopathic, familial or non-familial. Secondary erythromelalgia is associated with other diseases, the most common being MYELOPROLIFERATIVE DISORDERS.Ion Transport: The movement of ions across energy-transducing cell membranes. Transport can be active, passive or facilitated. Ions may travel by themselves (uniport), or as a group of two or more ions in the same (symport) or opposite (antiport) directions.Scorpions: Arthropods of the order Scorpiones, of which 1500 to 2000 species have been described. The most common live in tropical or subtropical areas. They are nocturnal and feed principally on insects and other arthropods. They are large arachnids but do not attack man spontaneously. They have a venomous sting. Their medical significance varies considerably and is dependent on their habits and venom potency rather than on their size. At most, the sting is equivalent to that of a hornet but certain species possess a highly toxic venom potentially fatal to humans. (From Dorland, 27th ed; Smith, Insects and Other Arthropods of Medical Importance, 1973, p417; Barnes, Invertebrate Zoology, 5th ed, p503)Semustine: 4-Methyl derivative of LOMUSTINE; (CCNU). An antineoplastic agent which functions as an alkylating agent.Transfection: The uptake of naked or purified DNA by CELLS, usually meaning the process as it occurs in eukaryotic cells. It is analogous to bacterial transformation (TRANSFORMATION, BACTERIAL) and both are routinely employed in GENE TRANSFER TECHNIQUES.Neurotoxins: Toxic substances from microorganisms, plants or animals that interfere with the functions of the nervous system. Most venoms contain neurotoxic substances. Myotoxins are included in this concept.Sodium, Dietary: Sodium or sodium compounds used in foods or as a food. The most frequently used compounds are sodium chloride or sodium glutamate.Electric Stimulation: Use of electric potential or currents to elicit biological responses.Kv1.1 Potassium Channel: A delayed rectifier subtype of shaker potassium channels that is commonly mutated in human episodic ATAXIA and MYOKYMIA.Sodium Chloride: A ubiquitous sodium salt that is commonly used to season food.Epithelial Sodium Channel Agonists: Compounds that either stimulate the opening or prevent closure of EPITHELIAL SODIUM ION CHANNELS.Doxorubicin: Antineoplastic antibiotic obtained from Streptomyces peucetius. It is a hydroxy derivative of DAUNORUBICIN.Kv1.3 Potassium Channel: A delayed rectifier subtype of shaker potassium channels that is the predominant VOLTAGE-GATED POTASSIUM CHANNEL of T-LYMPHOCYTES.Calcium Channel Agonists: Agents that increase calcium influx into calcium channels of excitable tissues. This causes vasoconstriction in VASCULAR SMOOTH MUSCLE and/or CARDIAC MUSCLE cells as well as stimulation of insulin release from pancreatic islets. Therefore, tissue-selective calcium agonists have the potential to combat cardiac failure and endocrinological disorders. They have been used primarily in experimental studies in cell and tissue culture.Myocardium: The muscle tissue of the HEART. It is composed of striated, involuntary muscle cells (MYOCYTES, CARDIAC) connected to form the contractile pump to generate blood flow.Cell Line, Tumor: A cell line derived from cultured tumor cells.TRPV Cation Channels: A subgroup of TRP cation channels named after vanilloid receptor. They are very sensitive to TEMPERATURE and hot spicy food and CAPSAICIN. They have the TRP domain and ANKYRIN repeats. Selectivity for CALCIUM over SODIUM ranges from 3 to 100 fold.Myotonia: Prolonged failure of muscle relaxation after contraction. This may occur after voluntary contractions, muscle percussion, or electrical stimulation of the muscle. Myotonia is a characteristic feature of MYOTONIC DISORDERS.Mutagenesis, Site-Directed: Genetically engineered MUTAGENESIS at a specific site in the DNA molecule that introduces a base substitution, or an insertion or deletion.RNA, Messenger: RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm.Barium: An element of the alkaline earth group of metals. It has an atomic symbol Ba, atomic number 56, and atomic weight 138. All of its acid-soluble salts are poisonous.Amino Acid Substitution: The naturally occurring or experimentally induced replacement of one or more AMINO ACIDS in a protein with another. If a functionally equivalent amino acid is substituted, the protein may retain wild-type activity. Substitution may also diminish, enhance, or eliminate protein function. Experimentally induced substitution is often used to study enzyme activities and binding site properties.Anesthetics, Local: Drugs that block nerve conduction when applied locally to nerve tissue in appropriate concentrations. They act on any part of the nervous system and on every type of nerve fiber. In contact with a nerve trunk, these anesthetics can cause both sensory and motor paralysis in the innervated area. Their action is completely reversible. (From Gilman AG, et. al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th ed) Nearly all local anesthetics act by reducing the tendency of voltage-dependent sodium channels to activate.TRPM Cation Channels: A subgroup of TRP cation channels named after melastatin protein. They have the TRP domain but lack ANKYRIN repeats. Enzyme domains in the C-terminus leads to them being called chanzymes.KCNQ1 Potassium Channel: A voltage-gated potassium channel that is expressed primarily in the HEART.Models, Molecular: Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures.Muscle Proteins: The protein constituents of muscle, the major ones being ACTINS and MYOSINS. More than a dozen accessory proteins exist including TROPONIN; TROPOMYOSIN; and DYSTROPHIN.Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability.Oxocins: Compounds based on an 8-membered heterocyclic ring including an oxygen. They can be considered medium ring ethers.Tetraethylammonium: A potassium-selective ion channel blocker. (From J Gen Phys 1994;104(1):173-90)Binding Sites: The parts of a macromolecule that directly participate in its specific combination with another molecule.Spider Venoms: Venoms of arthropods of the order Araneida of the ARACHNIDA. The venoms usually contain several protein fractions, including ENZYMES, hemolytic, neurolytic, and other TOXINS, BIOLOGICAL.Biophysics: The study of PHYSICAL PHENOMENA and PHYSICAL PROCESSES as applied to living things.KCNQ Potassium Channels: A family of delayed rectifier voltage-gated potassium channels that share homology with their founding member, KCNQ1 PROTEIN. KCNQ potassium channels have been implicated in a variety of diseases including LONG QT SYNDROME; DEAFNESS; and EPILEPSY.Marine Toxins: Toxic or poisonous substances elaborated by marine flora or fauna. They include also specific, characterized poisons or toxins for which there is no more specific heading, like those from poisonous FISHES.HEK293 Cells: A cell line generated from human embryonic kidney cells that were transformed with human adenovirus type 5.Cnidarian Venoms: Venoms from jellyfish; CORALS; SEA ANEMONES; etc. They contain hemo-, cardio-, dermo- , and neuro-toxic substances and probably ENZYMES. They include palytoxin, sarcophine, and anthopleurine.Kv1.5 Potassium Channel: A delayed rectifier subtype of shaker potassium channels that conducts a delayed rectifier current. It contributes to ACTION POTENTIAL repolarization of MYOCYTES in HEART ATRIA.Hydrogen-Ion Concentration: The normality of a solution with respect to HYDROGEN ions; H+. It is related to acidity measurements in most cases by pH = log 1/2[1/(H+)], where (H+) is the hydrogen ion concentration in gram equivalents per liter of solution. (McGraw-Hill Dictionary of Scientific and Technical Terms, 6th ed)Heart: The hollow, muscular organ that maintains the circulation of the blood.Chlorides: Inorganic compounds derived from hydrochloric acid that contain the Cl- ion.Tumor Stem Cell Assay: A cytologic technique for measuring the functional capacity of tumor stem cells by assaying their activity. It is used primarily for the in vitro testing of antineoplastic agents.Rats, Wistar: A strain of albino rat developed at the Wistar Institute that has spread widely at other institutions. This has markedly diluted the original strain.Guinea Pigs: A common name used for the genus Cavia. The most common species is Cavia porcellus which is the domesticated guinea pig used for pets and biomedical research.Protein Isoforms: Different forms of a protein that may be produced from different GENES, or from the same gene by ALTERNATIVE SPLICING.Tumor Cells, Cultured: Cells grown in vitro from neoplastic tissue. If they can be established as a TUMOR CELL LINE, they can be propagated in cell culture indefinitely.Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels: A subgroup of cyclic nucleotide-regulated ION CHANNELS of the superfamily of pore-loop cation channels that are opened by hyperpolarization rather than depolarization. The ion conducting pore passes SODIUM, CALCIUM, and POTASSIUM cations with a preference for potassium.Recombinant Proteins: Proteins prepared by recombinant DNA technology.Kv1.4 Potassium Channel: A fast inactivating subtype of shaker potassium channels that contains two inactivation domains at its N terminus.Biophysical Phenomena: The physical characteristics and processes of biological systems.Potassium Channels: Cell membrane glycoproteins that are selectively permeable to potassium ions. At least eight major groups of K channels exist and they are made up of dozens of different subunits.Shaw Potassium Channels: A shaker subfamily that is prominently expressed in NEURONS and are necessary for high-frequency, repetitive firing of ACTION POTENTIALS.Shab Potassium Channels: A subfamily of shaker potassium channels that shares homology with its founding member, Shab protein, Drosophila. They regulate delayed rectifier currents in the NERVOUS SYSTEM of DROSOPHILA and in the SKELETAL MUSCLE and HEART of VERTEBRATES.Small-Conductance Calcium-Activated Potassium Channels: A major class of calcium-activated potassium channels that are found primarily in excitable CELLS. They play important roles in the transmission of ACTION POTENTIALS and generate a long-lasting hyperpolarization known as the slow afterhyperpolarization.Mutation, Missense: A mutation in which a codon is mutated to one directing the incorporation of a different amino acid. This substitution may result in an inactive or unstable product. (From A Dictionary of Genetics, King & Stansfield, 5th ed)Rabbits: The species Oryctolagus cuniculus, in the family Leporidae, order LAGOMORPHA. Rabbits are born in burrows, furless, and with eyes and ears closed. In contrast with HARES, rabbits have 22 chromosome pairs.Cricetinae: A subfamily in the family MURIDAE, comprising the hamsters. Four of the more common genera are Cricetus, CRICETULUS; MESOCRICETUS; and PHODOPUS.Base Sequence: The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence.Drug Resistance, Multiple: Simultaneous resistance to several structurally and functionally distinct drugs.Structure-Activity Relationship: The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups.RNA, Complementary: Synthetic transcripts of a specific DNA molecule or fragment, made by an in vitro transcription system. This cRNA can be labeled with radioactive uracil and then used as a probe. (King & Stansfield, A Dictionary of Genetics, 4th ed)Electrophorus: A genus of fish, in the family GYMNOTIFORMES, capable of producing an electric shock that immobilizes fish and other prey. The species Electrophorus electricus is also known as the electric eel, though it is not a true eel.KCNQ2 Potassium Channel: A very slow opening and closing voltage-gated potassium channel that is expressed in NEURONS and is commonly mutated in BENIGN FAMILIAL NEONATAL CONVULSIONS.Lipid Bilayers: Layers of lipid molecules which are two molecules thick. Bilayer systems are frequently studied as models of biological membranes.Amphibian Proteins: Proteins obtained from species in the class of AMPHIBIANS.Kidney: Body organ that filters blood for the secretion of URINE and that regulates ion concentrations.SemicarbazonesAdenosine Triphosphate: An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate is a neurotransmitter.Transient Receptor Potential Channels: A broad group of eukaryotic six-transmembrane cation channels that are classified by sequence homology because their functional involvement with SENSATION is varied. They have only weak voltage sensitivity and ion selectivity. They are named after a DROSOPHILA mutant that displayed transient receptor potentials in response to light. A 25-amino-acid motif containing a TRP box (EWKFAR) just C-terminal to S6 is found in TRPC, TRPV and TRPM subgroups. ANKYRIN repeats are found in TRPC, TRPV & TRPN subgroups. Some are functionally associated with TYROSINE KINASE or TYPE C PHOSPHOLIPASES.Shal Potassium Channels: A shaker subfamily of potassium channels that participate in transient outward potassium currents by activating at subthreshold MEMBRANE POTENTIALS, inactivating rapidly, and recovering from inactivation quickly.Channelopathies: A variety of neuromuscular conditions resulting from MUTATIONS in ION CHANNELS manifesting as episodes of EPILEPSY; HEADACHE DISORDERS; and DYSKINESIAS.Muscle, Skeletal: A subtype of striated muscle, attached by TENDONS to the SKELETON. Skeletal muscles are innervated and their movement can be consciously controlled. They are also called voluntary muscles.Cesium: A member of the alkali metals. It has an atomic symbol Cs, atomic number 50, and atomic weight 132.91. Cesium has many industrial applications, including the construction of atomic clocks based on its atomic vibrational frequency.P-Glycoprotein: A 170-kDa transmembrane glycoprotein from the superfamily of ATP-BINDING CASSETTE TRANSPORTERS. It serves as an ATP-dependent efflux pump for a variety of chemicals, including many ANTINEOPLASTIC AGENTS. Overexpression of this glycoprotein is associated with multidrug resistance (see DRUG RESISTANCE, MULTIPLE).Brain: The part of CENTRAL NERVOUS SYSTEM that is contained within the skull (CRANIUM). Arising from the NEURAL TUBE, the embryonic brain is comprised of three major parts including PROSENCEPHALON (the forebrain); MESENCEPHALON (the midbrain); and RHOMBENCEPHALON (the hindbrain). The developed brain consists of CEREBRUM; CEREBELLUM; and other structures in the BRAIN STEM.Muscles: Contractile tissue that produces movement in animals.Phenotype: The outward appearance of the individual. It is the product of interactions between genes, and between the GENOTYPE and the environment.Anti-Arrhythmia Agents: Agents used for the treatment or prevention of cardiac arrhythmias. They may affect the polarization-repolarization phase of the action potential, its excitability or refractoriness, or impulse conduction or membrane responsiveness within cardiac fibers. Anti-arrhythmia agents are often classed into four main groups according to their mechanism of action: sodium channel blockade, beta-adrenergic blockade, repolarization prolongation, or calcium channel blockade.Synaptosomes: Pinched-off nerve endings and their contents of vesicles and cytoplasm together with the attached subsynaptic area of the membrane of the post-synaptic cell. They are largely artificial structures produced by fractionation after selective centrifugation of nervous tissue homogenates.Protein Binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments.Neurons, Afferent: Neurons which conduct NERVE IMPULSES to the CENTRAL NERVOUS SYSTEM.Cisplatin: An inorganic and water-soluble platinum complex. After undergoing hydrolysis, it reacts with DNA to produce both intra and interstrand crosslinks. These crosslinks appear to impair replication and transcription of DNA. The cytotoxicity of cisplatin correlates with cellular arrest in the G2 phase of the cell cycle.Cations: Positively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis.Cell Membrane Permeability: A quality of cell membranes which permits the passage of solvents and solutes into and out of cells.Insecticides: Pesticides designed to control insects that are harmful to man. The insects may be directly harmful, as those acting as disease vectors, or indirectly harmful, as destroyers of crops, food products, or textile fabrics.Protein Conformation: The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. PROTEIN STRUCTURE, QUATERNARY describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain).Gene Expression: The phenotypic manifestation of a gene or genes by the processes of GENETIC TRANSCRIPTION and GENETIC TRANSLATION.Reverse Transcriptase Polymerase Chain Reaction: A variation of the PCR technique in which cDNA is made from RNA via reverse transcription. The resultant cDNA is then amplified using standard PCR protocols.Long QT Syndrome: A condition that is characterized by episodes of fainting (SYNCOPE) and varying degree of ventricular arrhythmia as indicated by the prolonged QT interval. The inherited forms are caused by mutation of genes encoding cardiac ion channel proteins. The two major forms are ROMANO-WARD SYNDROME and JERVELL-LANGE NIELSEN SYNDROME.Large-Conductance Calcium-Activated Potassium Channel alpha Subunits: The pore-forming subunits of large-conductance calcium-activated potassium channels. They form tetramers in CELL MEMBRANES.Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.Ciguatoxins: Polycyclic ethers produced by Gambierdiscus (DINOFLAGELLATES) from gambiertoxins, which are ingested by fish which in turn may be ingested by humans who are susceptible to the CIGUATERA POISONING.Tetraethylammonium CompoundsElectrophysiological Phenomena: The electrical properties, characteristics of living organisms, and the processes of organisms or their parts that are involved in generating and responding to electrical charges.Brugada Syndrome: An autosomal dominant defect of cardiac conduction that is characterized by an abnormal ST-segment in leads V1-V3 on the ELECTROCARDIOGRAM resembling a right BUNDLE-BRANCH BLOCK; high risk of VENTRICULAR TACHYCARDIA; or VENTRICULAR FIBRILLATION; SYNCOPAL EPISODE; and possible sudden death. This syndrome is linked to mutations of gene encoding the cardiac SODIUM CHANNEL alpha subunit.Antimalarials: Agents used in the treatment of malaria. They are usually classified on the basis of their action against plasmodia at different stages in their life cycle in the human. (From AMA, Drug Evaluations Annual, 1992, p1585)Drug Evaluation, Preclinical: Preclinical testing of drugs in experimental animals or in vitro for their biological and toxic effects and potential clinical applications.G Protein-Coupled Inwardly-Rectifying Potassium Channels: A family of inwardly-rectifying potassium channels that are activated by PERTUSSIS TOXIN sensitive G-PROTEIN-COUPLED RECEPTORS. GIRK potassium channels are primarily activated by the complex of GTP-BINDING PROTEIN BETA SUBUNITS and GTP-BINDING PROTEIN GAMMA SUBUNITS.Ankyrins: A family of membrane-associated proteins responsible for the attachment of the cytoskeleton. Erythrocyte-related isoforms of ankyrin attach the SPECTRIN cytoskeleton to a transmembrane protein (ANION EXCHANGE PROTEIN 1, ERYTHROCYTE) in the erythrocyte plasma membrane. Brain-related isoforms of ankyrin also exist.Ryanodine Receptor Calcium Release Channel: A tetrameric calcium release channel in the SARCOPLASMIC RETICULUM membrane of SMOOTH MUSCLE CELLS, acting oppositely to SARCOPLASMIC RETICULUM CALCIUM-TRANSPORTING ATPASES. It is important in skeletal and cardiac excitation-contraction coupling and studied by using RYANODINE. Abnormalities are implicated in CARDIAC ARRHYTHMIAS and MUSCULAR DISEASES.Paralyses, Familial Periodic: A heterogenous group of inherited disorders characterized by recurring attacks of rapidly progressive flaccid paralysis or myotonia. These conditions have in common a mutation of the gene encoding the alpha subunit of the sodium channel in skeletal muscle. They are frequently associated with fluctuations in serum potassium levels. Periodic paralysis may also occur as a non-familial process secondary to THYROTOXICOSIS and other conditions. (From Adams et al., Principles of Neurology, 6th ed, p1481)Blotting, Western: Identification of proteins or peptides that have been electrophoretically separated by blot transferring from the electrophoresis gel to strips of nitrocellulose paper, followed by labeling with antibody probes.Sequence Homology, Amino Acid: The degree of similarity between sequences of amino acids. This information is useful for the analyzing genetic relatedness of proteins and species.Verapamil: A calcium channel blocker that is a class IV anti-arrhythmia agent.Cloning, Molecular: The insertion of recombinant DNA molecules from prokaryotic and/or eukaryotic sources into a replicating vehicle, such as a plasmid or virus vector, and the introduction of the resultant hybrid molecules into recipient cells without altering the viability of those cells.ATP-Binding Cassette Transporters: A family of MEMBRANE TRANSPORT PROTEINS that require ATP hydrolysis for the transport of substrates across membranes. The protein family derives its name from the ATP-binding domain found on the protein.Signal Transduction: The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway.Calcium Channels, P-Type: CALCIUM CHANNELS located within the PURKINJE CELLS of the cerebellum. They are involved in stimulation-secretion coupling of neurons.Acetanilides: Compounds based on N-phenylacetamide, that are similar in structure to 2-PHENYLACETAMIDES. They are precursors of many other compounds. They were formerly used as ANALGESICS and ANTIPYRETICS, but often caused lethal METHEMOGLOBINEMIA.Mollusk Venoms: Venoms from mollusks, including CONUS and OCTOPUS species. The venoms contain proteins, enzymes, choline derivatives, slow-reacting substances, and several characterized polypeptide toxins that affect the nervous system. Mollusk venoms include cephalotoxin, venerupin, maculotoxin, surugatoxin, conotoxins, and murexine.Kidney Tubules, Collecting: Straight tubes commencing in the radiate part of the kidney cortex where they receive the curved ends of the distal convoluted tubules. In the medulla the collecting tubules of each pyramid converge to join a central tube (duct of Bellini) which opens on the summit of the papilla.KCNQ3 Potassium Channel: A very slow opening and closing voltage-gated potassium channel that is expressed in NEURONS and is closely related to KCNQ2 POTASSIUM CHANNEL. It is commonly mutated in BENIGN FAMILIAL NEONATAL CONVULSIONS.

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"Blockers of Voltage-Gated Sodium Channels for the Treatment of Central Nervous System Diseases". Recent Patents on CNS Drug ... Invertebrates possess two Nav channels (Nav1 and Nav2), whereas vertebrate Nav channels are of the Nav1 family. Sodium-channel ... Vornanen M, Hassinen M, Haverinen J (2011). "Tetrodotoxin sensitivity of the vertebrate cardiac Na+ current". Marine Drugs. 9 ( ... "Voltage gated", also called "voltage sensitive" and "voltage dependant" sodium channel also known as "VGSCs" or "Nav channel" ...
Looking for online definition of Voltage-gated sodium channel subunit alpha Nav1.6 in the Medical Dictionary? Voltage-gated sodium channel subunit alpha Nav1.6 explanation free. What is Voltage-gated sodium channel subunit alpha Nav1.6? Meaning of Voltage-gated sodium channel subunit alpha Nav1.6 medical term. What does Voltage-gated sodium channel subunit alpha Nav1.6 mean?
Title: Voltage-Gated Sodium Channel Blockers; Target Validation and Therapeutic Potential. VOLUME: 5 ISSUE: 6. Author(s): John N. Wood and James Boorman. Affiliation:Molecular Nociception Group, Biology UCL, Gower Street, London WC1 E 6BT.. Abstract: Voltage-gated sodium channels are encoded by a family of ten structurally-related genes that are expressed in spatially and temporally distinct patterns, mainly in excitable tissues. They underlie electrical signalling in nerve and muscle. It has long been known that sodium channel blockers are anaesthetics as well as powerful analgesics when delivered at low concentrations. In addition, cardiac arrhythmias and epileptic activity can be treated with sodium channel blockers. As we have learned more about the sub-types of sodium ...
To study the effect of autoimmunity against the alpha subunit of cardiac voltage-gated sodium channel NaV1.5 in vivo, an autoimmune response was induced in rats through immunization with a NaV1.5-peptide. Consequently, high levels of autoantibodies targeting the third extracellular loop of the first domain could be detected in blood, reflecting successful immunization. Immunized animals developed an exclusively electrical phenotype with conduction defects on the sinoatrial and the atrioventricular level without signs of structural heart disease or myocardial inflammation. On the cellular level, this phenotype is probably caused by a reduced density of INa in cardiomyocytes.. The NaV1.5 is composed of 4 structurally homologous domains (DI-DIV) each consisting of 6 transmembrane segments (S1-S6) (14). The residues between S5 and S6 form the channel pore (P loop) and control ...
TY - JOUR. T1 - Neuronal voltage-gated sodium channel subtypes. T2 - Key roles in inflammatory and neuropathic pain. AU - Ekberg, J.. AU - Adams, David J.. PY - 2006. Y1 - 2006. N2 - Voltage-gated sodium channels (VGSCs) play an important role in neuronal excitability. Regulation of VGSC activity is a complex phenomenon that occurs at multiple levels in the cell, including transcriptional regulation, post-translational modification and membrane insertion and retrieval. Multiple VGSC subtypes exist that vary in their biophysical and pharmacological properties and tissue distribution. Any alteration of the VGSC subtype profile of a neuron or the mechanisms that regulate VGSC activity can cause significant changes in neuronal excitability. Inflammatory and neuropathic pain states are characterised by alterations in VGSC subtype composition and activity in sensory neurons. This ...
Voltage-gated ion channels allow electrically excitable cells to generate and propagate action potentials and therefore are crucial for nerve and muscle function. Sodium channels play a special role by mediating rapid depolarization, which constitutes the rising phase of the action potential and in turn activates voltage-gated calcium and potassium channels. Voltage-gated sodium channels represent a multigene family. Nine sodium channel subtypes have been cloned and functionally expressed to date. [Clare, J. J., Tate, S. N., Nobbs, M. & Romanes, M. A. Voltage-gated sodium channels as therapeutic targets. Drug Discovery Today 5, 506-520 (2000)]. They are differentially expressed throughout ...
TY - JOUR. T1 - Voltage-dependent sodium channel function is regulated through membrane mechanics. AU - Shcherbatko, Anatoly. AU - Ono, Fumihito. AU - Mandel, Gail. AU - Brehm, Paul. PY - 1999/10. Y1 - 1999/10. N2 - Cut-open recordings from Xenopus oocytes expressing either nerve (PN1) or skeletal muscle (SkM1) Na+ channel α subunits revealed slow inactivation onset and recovery kinetics of inward current. In contrast, recordings using the macropatch configuration resulted in an immediate negative shift in the voltage-dependence of inactivation and activation, as well as time-dependent shifts in kinetics when compared to cut-open recordings. Specifically, a slow transition from predominantly slow onset and recovery to exclusively fast onset and fast recovery from inactivation occurred. The shift to fast inactivation was accelerated by patch excision and by agents that disrupted microtubule formation. Application of positive ...
Two point linkage analysis yielded a maximum lod score (Zmax) of 2.11 at θ = 0 for both markers D2S2370 and D2S2330. Critical recombination events occurring in individual II-3 and III-1 indicate that marker D2S2345 defines the telomeric end. This marker and marker D2S2370, which is reported by the literature7 as the centromeric boundary, limit the responsible gene to a region of 5.98 cM (fig 2). Individual III-5 (3 years old) carried the risk haplotype but was clinically unaffected, possibly due to the late onset of the disease, because all of the affected individuals in this family first showed symptoms at 7-15 years old, and we have not found patients less than 5 years old in the literature.3,8. This genomic interval contains a cluster of sodium channel genes including SCN1A, SCN2A, SCN3A, SCN7A, and SCN9A. Primary erythermalgia can be evoked by various stimulations, comparable to sodium channel diseases such as severe myoclonic epilepsy ...
Polymorphism H558R in the human cardiac sodium channel SCN5A gene is associated with atrial fibrillation.: Atrial fibrillation (AF) is one of the most common su
Ionic channel activity is involved in fundamental cellular behaviour and participates in cancerous features such as proliferation, migration and invasion which in turn contribute to the metastatic process. In this study, we investigated the expression and role of voltage-gated sodium channels in non-small-cell lung cancer cell lines. Functional voltage-gated sodium channels expression was investigated in normal and non-small-cell lung cancer cell lines. The measurement, in patch-clamp conditions, of tetrodotoxin-inhibitable sodium currents indicated that the strongly metastatic cancerous cell lines H23, H460 and Calu-1 possess functional sodium channels while normal and weakly metastatic cell lines do not. While all the cell lines expressed mRNA for numerous ...
We studied the relation of the maximal upstroke velocity (Vmax) of action potentials to the peak sodium current (INa) under voltage clamp in single, internally perfused, canine cardiac Purkinje cells under conditions that ensured membrane action potentials due only to INa. Three different methods of altering sodium channel availability were investigated: voltage-dependent inactivation, tetrodotoxin (TTX) block, and use-dependent block by quinidine. Under all three conditions, the relation of Vmax to INa was nonlinear, and no relation was found that would allow prediction of INa results from Vmax measurements. With voltage-dependent inactivation or TTX block, sodium channel availability measured by Vmax was reduced less than availability measured by peak INa, so that Vmax overestimated sodium channel availability. This ...
Navα1.2, also known as the sodium channel, voltage-gated, type II, alpha subunit is a protein that in humans is encoded by the SCN2A gene. Functional sodium channels contain an ion conductive alpha subunit and one or more regulatory beta subunits. Sodium channels which contain the Navα1.2 subunit are called Nav1.2 channels. Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with four domains including 24 transmembrane segments and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family. It is ...
Bisphenol A (BPA) has attracted considerable public attention as it leaches from plastic used in food containers, is detectable in human fluids and recent epidemiologic studies link BPA exposure with diseases including cardiovascular disorders. As heart-toxicity may derive from modified cardiac electrophysiology, we investigated the interaction between BPA and hNav1.5, the predominant voltage-gated sodium channel subtype expressed in the human heart. Electrophysiology studies of heterologously-expressed hNav1.5 determined that BPA blocks the channel with a Kd of 25.4±1.3 µM. By comparing the effects of BPA and the local anesthetic mexiletine on wild type hNav1.5 and the F1760A mutant, we demonstrate that both compounds share an overlapping binding site. With a key binding determinant thus identified, an homology model of hNav1.5 was ...
Arginine methylation is a novel post-translational modification within the voltage-gated ion channel superfamily, including the cardiac sodium channel, Nav1.5. We show that Nav1.5 R513 methylation decreases S516 phosphorylation rate by 4 orders of magnitude, the first evidence of protein kinase A inhibition by arginine methylation. Reciprocally, S516 phosphorylation blocks R513 methylation. Nav1.5 p.G514C, associated to cardiac conduction disease, abrogates R513 methylation, while leaving S516 phosphorylation rate unchanged. This is the first report of methylation-phosphorylation cross-talk of a cardiac ion channel[-] ...
The (−)-gallocatechin-3-gallate (GCG) concentration in some tea beverages can account for as much as 50% of the total catechins. It has been shown that catechins have analgesic properties. Voltage-gated sodium channels (Nav) mediate neuronal action potentials. Tetrodotoxin inhibits all Nav isoforms, but Nav1.8 and Nav1.9 are relatively tetrodotoxin-resistant compared to other isoforms and functionally linked to nociception. In this study, the effects of GCG on tetrodotoxin-resistant Na+ currents were investigated in rat primary cultures of dorsal root ganglion neurons via the whole-cell patch-clamp technique. We found that 1 μM GCG reduced the amplitudes of peak current density of tetrodotoxin-resistant Na+ currents significantly. Furthermore, the inhibition was accompanied by a depolarizing shift of the activation voltage and a ...
Background: Mutations in voltage gated brain sodium channel Nav1.1 have been linked to many disorders, including Generalized Epilepsy with Febrile Seizures Plus (GEFS+) and Severe Myoclonic Epilepsy of Infancy (SMEI). Recent studies have identified TTX- sensitive Nav1.1 brain sodium channels in the SA node and ventricular T-tubules of the heart, though their role in cardiac function is still controversial. We tested the functional significance of Nav1.1 sodium channels in the heart by creating a novel knock-in of human epilepsy GEFS+ mutation SCN1A-R1648H at the Scn1a locus of a C57BL/6J X 129 mouse.. Method: In vivo 2-D echocardiography was performed on 2 week old (juvenile) and 8 week old (adult) wild-type and heterozygote (Scn1aRH/+) mice after extracardiac neuronal block through intraperitoneal injections of atropine and ...
Voltage-dependent sodium channels are heteromeric complexes that regulate sodium exchange between intracellular and extracellular spaces and are essential for the generation and propagation of action potentials in muscle cells and neurons. Each sodium channel is composed of a large pore-forming, glycosylated alpha subunit and two smaller beta subunits. This gene encodes a sodium channel alpha subunit, which has four homologous domains, each of which contains six transmembrane regions. Allelic variants of this gene are associated with generalized epilepsy with febrile seizures and epileptic encephalopathy. Alternative splicing results in multiple transcript variants. The RefSeq Project has decided to create four representative RefSeq records. Three of the transcript variants are supported by experimental evidence and the fourth contains alternate 5 untranslated exons, the ...
TY - JOUR. T1 - The human Nav1.5 F1486 deletion associated with long QT syndrome leads to impaired sodium channel inactivation and reduced lidocaine sensitivity. AU - Song, Weihua. AU - Xiao, Yucheng. AU - Chen, Hanying. AU - Ashpole, Nicole M.. AU - Piekarz, Andrew D.. AU - Ma, Peilin. AU - Hudmon, Andy. AU - Cummins, Theodore R.. AU - Shou, Weinian. PY - 2012/10/1. Y1 - 2012/10/1. N2 - The deletion of phenylalanine 1486 (F1486del) in the human cardiac voltage-gated sodium channel (hNav1.5) is associated with fatal long QT (LQT) syndrome. In this study we determined how F1486del impairs the functional properties of hNav1.5 and alters action potential firing in heterologous expression systems (human embryonic kidney (HEK) 293 cells) and their native cardiomyocyte background. Cells expressing hNav1.5-F1486del exhibited a ...
Background: Gain-of-function mutations of the nociceptive voltage-gated sodium channel Nav1.7 lead to inherited pain syndromes, such as paroxysmal extreme pain disorder (PEPD). One characteristic of these mutations is slowed fast-inactivation kinetics, which may give rise to resurgent sodium currents. It is long known that toxins from Anemonia sulcata, such as ATX-II, slow fast inactivation and skin contact for example during diving leads to various symptoms such as pain and itch. Here, we investigated if ATX-II induces resurgent currents in sensory neurons of the dorsal root ganglion (DRGs) and how this may translate into human sensations. Results: In large A-fiber related DRGs ATX-II (5 nM) enhances persistent and resurgent sodium currents, but failed to do so in small C-fiber linked DRGs when investigated using the whole-cell patch-clamp technique. ...
Expression of the α-subunit of the amiloride-sensitive sodium channel (αENaC) is regulated by a number of factors in the lung, including oxygen partial pressure (Po2). As transcriptional activation is a mechanism for raising cellular mRNA levels, we investigated the effect of physiological changes in Po2 on the activity of the redox-sensitive transcription factor nuclear factor κB (NF-κB) and transcriptional activity of 5′-flanking regions of the human αENaC gene using luciferase reporter-gene vectors transiently transfected into human adult alveolar carcinoma A549 cells. By Western blotting we confirmed the presence of NF-κB p65 but not p50 in these cells. Transiently increasing Po2 from 23 to 42mmHg for 24h evoked a significant increase in NF-κB DNA-binding activity and transactivation of a NF-κB-driven luciferase construct (pGLNF-κBpro), which was blocked by the NF-κB activation inhibitor sulphasalazine (5mM). Transcriptional activity of αENaC-luciferase ...
Inside the organism, changes in pH levels occur under pathophysiological conditions such as inflammation, ischemia, cancer, and the like, which are accompanied by pain. The Acid-sensing Ion Channel (ASIC) detects changes in pH levels in the organism and transmits the pain signal to the brain. Biologically, many studies have been conducted regarding the Acid-sensing Ion Channel; however, many areas are still unclear, especially in terms of the operational mechanism and the cell membrane merging mechanism. Professor Suhs research team detected the cell membrane merging mechanisms that modulate the activity of the Acid-sensing Ion Channel at the molecular level, and it is this discovery and identification of the new cell membrane merging mechanism of the Acid-sensing Ion Channel that had remained unknown until now. The research team identified through animal experiments that there is a different cell membrane merging mechanism between subunits ...
The epithelial sodium channel (short: ENaC, also: amiloride-sensitive sodium channel) is a membrane-bound ion channel that is selectively permeable to Na+ ions and that is assembled as a heterotrimer composed of three homologous subunits α or δ, β, and γ, These subunits are encoded by four genes: SCNN1A, SCNN1B, SCNN1G, and SCNN1D. It is involved primarily in the reabsorption of sodium ions at the collecting ducts of the kidneys nephrons. The apical membranes of many tight epithelia contain sodium channels that are characterized primarily by their high affinity for the diuretic blocker amiloride. These channels mediate the first step of active sodium reabsorption essential for the maintenance of body salt and water homeostasis. In vertebrates, the channels control reabsorption of sodium in kidney, colon, ...
TY - JOUR. T1 - A novel tumor necrosis factor-mediated mechanism of direct epithelial sodium channel activation. AU - Czikora, István. AU - Alli, Abdel. AU - Bao, Hui Fang. AU - Kaftan, David. AU - Sridhar, Supriya. AU - Apell, Hans Jürgen. AU - Gorshkov, Boris. AU - White, Richard. AU - Zimmermann, Astrid. AU - Wendel, Albrecht. AU - Pauly-Evers, Meike. AU - Hamacher, Jürg. AU - Garcia-Gabay, Irène. AU - Fischer, Bernhard. AU - Verin, Alexander. AU - Bagi, Zsolt. AU - Pittet, Jean Francois. AU - Shabbir, Waheed. AU - Lemmens-Gruber, Rosa. AU - Chakraborty, Trinad. AU - Lazrak, Ahmed. AU - Matthay, Michael A.. AU - Eaton, Douglas C.. AU - Lucas, Rudolf. PY - 2014/9/1. Y1 - 2014/9/1. N2 - Rationale: Alveolar liquid clearance is regulated by Na+ uptake through the apically expressed epithelial sodium channel (ENaC) and basolaterally localized Na+-K+-ATPase in type II alveolar epithelial cells. Dysfunction of these Na+ transporters during ...
TY - JOUR. T1 - Stimulatory action of telmisartan, an antagonist of angiotensin II receptor, on voltage-gated Na + current. T2 - Experimental and theoretical studies. AU - Chang, Tzu Tung. AU - Yang, Chia Jung. AU - Lee, Yu Chi. AU - Wu, Sheng-Nan. PY - 2018/1/1. Y1 - 2018/1/1. N2 - Telmisartan (Tel) is recognized as a non-peptide blocker of AT1R. Whether this agent has any direct effects on ion currents remains unexplored. In whole-cell current recordings, addition of Tel increased the peak amplitude of voltage-gated Na + (Na V ) current (I Na ) accompanied by the increased time constant of I Na inactivation in differentiated NSC-34 motor neuron-like cells. Tel-stimulated INa in these cells is unlinked to either blockade of AT1R or activation of peroxisome proliferator-activated receptor gamma (PPAR-γ). In order to explore how this compound affects the amplitude and kinetics of I Na in neurons, a Hodgkin-Huxley-based (HH-based) model ...
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TY - JOUR. T1 - Molecular motions of the outer ring of charge of the sodium channel. T2 - Do they couple to slow inactivation?. AU - Xiong, Wei. AU - Li, Ronald A.. AU - Tian, Yanli. AU - Tomaselli, Gordon F.. PY - 2003/9/1. Y1 - 2003/9/1. N2 - In contrast to fast inactivation, the molecular basis of sodium (Na) channel slow inactivation is poorly understood. It has been suggested that structural rearrangements in the outer pore mediate slow inactivation of Na channels similar to C-type inactivation in potassium (K) channels. We probed the role of the outer ring of charge in inactivation gating by paired cysteine mutagenesis in the rat skeletal muscle Na channel (rNav1.4). The outer charged ring residues were substituted with cysteine, paired with cysteine mutants at other positions in the external pore, and coexpressed with rat brain β 1 in Xenopus oocytes. Dithiolthreitol ...
Background- We and others have reported mutations in the cardiac predominant sodium channel gene SCN5A in patients with atrial fibrillation (AF). We also have reported that SCN1B is associated with Brugada syndrome and isolated cardiac conduction disease. We tested the hypothesis that mutations in the 4 sodium channel β-subunit genes SCN1B-SCN4B contribute to AF susceptibility.. Methods and Results- Screening for mutations in the 4 β-subunit genes was performed in 480 patients with AF (118 patients with lone AF and 362 patients with AF and cardiovascular disease) and 548 control subjects (188 ethnically defined anonymized subjects and 360 subjects without AF). The effects of mutant β-subunits on SCN5A mediated currents were studied using electrophysiological studies. We identified 2 nonsynonymous variants in SCN1B (resulting in R85H, D153N) and 2 in SCN2B (R28Q, R28W) in patients with AF. These occur at residues highly conserved across ...
Statement of the problem: The epithelial sodium channels (ENaC) play an important role in regulation of blood pressure (BP). Although the genes are identical in Dahl salt sensitive (S) and Dahl salt resistant (R) rats, expression of ENaC subunits is increased in kidneys of S rats on high salt diet. Intracerebroventricular (icv) infusion of ENaC blocker benzamil prevents Na+ induced hypertension. It was not known whether ENaC subunits are expressed in the brain and whether or not brain ENaC plays a role in regulation of [Na+] in CNS. Hypothesis: 1. Epithelial sodium channels are expressed in the brain. 2. Expression of ENaC is increased in the kidneys and brain of Dahl S rats on high salt diet. 3. ENaC in the brain contributes to regulation of [Na+] in the CSF and brain interstitium. Methods of investigation: We studied expression and distribution of the ENaC subunits and assessed the effects of icv infusion of Na+-rich aCSF in Wistar rats or ...
Dendritic spines mediate most excitatory synapses in the brain. Past theoretical work and recent experimental evidence have suggested that spines could contain sodium channels. We tested this by measuring the effect of the sodium channel blocker tetrodotoxin (TTX) on depolarizations generated by two-photon uncaging of glutamate on spines from mouse neocortical pyramidal neurons. In practically all spines examined, uncaging potentials were significantly reduced by TTX. This effect was postsynaptic and spatially localized to the spine and occurred with uncaging potentials of different amplitudes and in spines of different neck lengths. Our data confirm that spines from neocortical pyramidal neurons are electrically isolated from the dendrite and indicate that they have sodium channels and are therefore excitable structures. Spine sodium channels could boost synaptic potentials ...
Pyrethroid insecticides are known to modify neuronal sodium channels, inducing persistent, steady-state sodium current at depolarized membrane potentials. Cardiac myocytes are also rich in sodium channels but comparatively little is known about the effect of pyrethroids on the heart, or on the cardiac sodium channel isoform. In the present study therefore, we determined the actions of type I and type II pyrethroids against rat and guinea pig ventricular myocytes under current and voltage clamp, and on isolated perfused rat hearts. In myocytes, tefluthrin (type I) and fenpropathrin and alpha-cypermethrin (type II) prolonged action potentials and evoked afterdepolarizations. The time course of sodium current (I(Na)) was also prolonged by these compounds. Pyrethroids delayed I(Na) inactivation, when measured under selective conditions as current sensitive to 30 ...
Pyrethroid insecticides are known to modify neuronal sodium channels, inducing persistent, steady-state sodium current at depolarized membrane potentials. Cardiac myocytes are also rich in sodium channels but comparatively little is known about the effect of pyrethroids on the heart, or on the cardiac sodium channel isoform. In the present study therefore, we determined the actions of type I and type II pyrethroids against rat and guinea pig ventricular myocytes under current and voltage clamp, and on isolated perfused rat hearts. In myocytes, tefluthrin (type I) and fenpropathrin and alpha-cypermethrin (type II) prolonged action potentials and evoked afterdepolarizations. The time course of sodium current (I(Na)) was also prolonged by these compounds. Pyrethroids delayed I(Na) inactivation, when measured under selective conditions as current sensitive to 30 ...
Introduction: Mutations in the voltage-gated sodium channel SCN1A gene are the main genetic cause of Dravet syndrome (previously called Severe Myoclonic Epilepsy of Infancy or SMEI).. Objective and methods: Our objectives were to characterize in more detail the mutation spectrum associated with Introduction. Mutations in the voltage-gated sodium channel SCN1A gene are the main genetic cause of Dravet syndrome (previously called Severe Myoclonic Epilepsy of Infancy or SMEI).. Objective and methods: Our objectives were to characterize in more detail the mutation spectrum associated with Dravet syndrome by screening a large series of 333 patients using both direct sequencing and Multiplex Ligation-dependent probe Amplification (MLPA). Additionally, we screened non-coding regions of the gene that are usually not investigated.. Results: SCN1A point mutations were ...
The amiloride-sensitive epithelial sodium channel (ENaC) is a heteromultimer of three homologous subunits (alpha-, beta-, and gamma- subunits). To study the role of the beta-subunit in vivo, we analyzed mice in which the betaENaC gene locus was disrupted. These mice showed low levels of betaENaC mRNA expression in kidney (approximately 1%), lung (approximately 1%), and colon (approximately 4%). In homozygous mutant betaENaC mice, no betaENaC protein could be detected with immunofluorescent staining. At birth, there was a small delay in lung- liquid clearance that paralleled diminished amiloride-sensitive Na+ absorption in tracheal explants. With normal salt intake, these mice showed a normal growth rate. However, in vivo, adult betaENaC m/m mice exhibited a significantly reduced ENaC activity in colon and elevated plasma aldosterone levels, suggesting hypovolemia and pseudohypoaldosteronism type 1. This phenotype was clinically silent, as betaENaC m/m mice showed no weight ...
In this issue of the Journal, McNair et al. (12) report the screening of the cardiac sodium channel gene SCN5A in a cohort of patients and families with DCM. Of the 338 subjects from 289 families studied, 15 mutation carriers were found, including 5 separate mutations (1.7%), 3 being novel (12). In 14 of 15 subjects with mutations (93%), arrhythmias were also notable and included supraventricular arrhythmias (13 of 15), sick sinus syndrome (5 of 15), atrial fibrillation (9 of 15), ventricular tachycardia (5 of 15), and conduction disease (9 of 15). The authors have studied the mechanisms involved in the development of these overlapping phenotypes. In nearly 70% of the SCN5A mutations thus far reported to cause DCM, the mutations localize to the highly conserved homologous S3 and S4 transmembrane segments, suggesting a shared mechanism of disruption of the voltage-sensing mechanism of this channel. Hence, the authors intimate a correlation ...
The discovery of genetic variants that substantially alter an individuals perception of pain has led to a step-change in our understanding of molecular events underlying the detection and transmission of noxious stimuli by the peripheral nervous system. For example, the voltage-gated sodium ion channel Na v 1.7 is expressed selectively in sensory and autonomic neurons; inactivating mutations in SCN9A, which encodes Na v 1.7, result in congenital insensitivity to pain, whereas gain-of-function mutations in this gene produce distinct pain syndromes such as inherited erythromelalgia, paroxysmal extreme pain disorder, and smal l-fibre neuropathy. Heterozygous mutations in TRPA1, which encodes the transient receptor potential cation channel, can cause familial episodic pain syndromes, and variants of genes coding for the voltage-gated sodium ...
TY - JOUR. T1 - Functional consequences of a Na+ channel mutation causing hyperkalemic periodic paralysis. AU - Cummins, Theodore R.. AU - Zhou, Jiuying. AU - Sigworth, Frederick J.. AU - Ukomadu, Chinwe. AU - Stephan, Megan. AU - Ptáčk, Louis J.. AU - Agnew, William S.. PY - 1993/4. Y1 - 1993/4. N2 - Hyperkalemic periodic paralysis (HYPP), one of several inheritable myotonic diseases, results from genetic defects in the human skeletal muscle Na+ channel. In some pedigrees, HYPP is correlated with a single base pair substitution resulting in a Met replacing Thr704 in the fifth transmembrane segment of the second domain. This region is totally conserved between the human and rat channels. We have introduced the human mutation into the corresponding region of the rat muscle Na+ channel cDNA and expressed it in human embryonic kidney 293 cells. Patch-clamp recordings show that this mutation shifts the voltage dependence of ...
Introduction: Brugada syndrome (BrS) is an oligogenic disease, often linked to mutations in SCN5A encoding the canonical cardiac sodium channel. Prolongation of QRS interval implicates slowed cardiac conduction as an important element of the BrS arrhythmia phenotype. Recent genome-wide association studies have implicated common variation in SCN10A as a potential modulator of cardiac conduction. SCN10A encodes the tetrodotoxin-resistant voltage-gated sodium channel isoform Nav1.8 primarily found in dorsal root ganglia and at lower levels in the heart. A recent candidate gene sequencing study identified 5 non-synonymous SCN10A rare variants in 4/156 white SCN5A mutation-negative patients with BrS and one protective non-synonymous common variant V1073A [(T,C): T allele BrS vs. control: 65.1% vs. 40.1%, P = 3.54x10-19].. Hypothesis: Here we tested the hypothesis that the common variant (V1073A) ...
Epithelial Na+ channels historically have been classified according to their kinetics, pharmacology, and single channel conductance (see Palmer, 1992; Smith and Benos, 1991). The molecular identity of these channels was unknown until the cloning of the Na(5) channel (classification of Palmer, 1992) independently by Canessa et al. (1993, 1994), by Lingueglia et al. (1993), and Voilley et al. (1994). This channel is also referred to as the epithelial Na+ channel (ENaC)1 and is characterized by a 5-pS single channel conductance, long open and close times, high amiloride sensitivity (Ki , 100 nM), and high Na+ to K+ selectivity. ENaC is composed of three subunits, α, β, and γ, that are necessary to reconstitute the in vivo single channel properties and maximal amiloride-sensitive currents in Xenopus oocytes (Canessa et al., 1994).. The epithelial Na+ ...
Voltage-gated sodium channels (VGSCs) play a central role in the generation and propagation of action potentials in excitable neurons and other cells and are targeted by commonly used local anesthetics, antiarrhythmics, and anticonvulsants. They are also common targets of neurotoxins including shellfish toxins. Shellfish toxins are a variety of toxic secondary metabolites produced by prokaryotic cyanobacteria and eukaryotic dinoflagellates in both marine and fresh water systems, which can accumulate in marine animals via the food chain. Consumption of shellfish toxin-contaminated seafood may result in potentially fatal human shellfish poisoning. This article provides an overview of the structure, bioactivity, and pharmacology of shellfish toxins that act on VGSCs, along with a brief discussion on their pharmaceutical potential for pain management.
The amiloride-sensitive epithelial sodium channel is a highly selective sodium channel that constitutes the rate-limiting step of sodium reabsorption in distal nephrons. It consists of at least 3 subunits (a, /?, and y) of similar structure and plays an important role in sodium and fluid homeostasis. Defects of this channel have been critically implicated in Liddle syndrome (pseudoaldosteronism) and pseudohypoaldosteronism type 1. A sample of 48 individuals from 23 nuclear families was selected from Anhui, China. We sequenced 12 exons and flanking intronic sequences and discovered a new 207-bp intron located in the previously described exon X of Thomas et al. (1996). In addition, 4 novel single nucleotide polymorphisms were identified; 3 were in exon 3 and 1 was in exon 13. Furthermore, 2 base substitutions in exon 13 were present in all the Chinese subjects compared with the published ...
Inhibits tetrodotoxin-sensitive voltage-gated sodium channels (Nav) by binding to site 3. Slows the inactivation, and causes a prolongation of action potential duration resulting in repetitive firing in autonomic and motor nerve fibers. Does not depolarize the resting potential. Does not affect tetrodotoxin-resistant sodium channels. This lethal neurotoxin is active on both insect and mammalian voltage-gated sodium channels. Pan-neuronal expression in Drosophila is lethal but flies engineered to express the toxin only in pacemaker neurons have profound defects in circadian rhythm but a normal lifespan.
Hyperkalemic periodic paralysis (HyperKPP) produces myotonia and attacks of muscle weakness triggered by rest after exercise or by K+ ingestion. We introduced a missense substitution corresponding to a human familial HyperKPP mutation (Met1592Val) into the mouse gene encoding the skeletal muscle voltage-gated Na+ channel NaV1.4. Mice heterozygous for this mutation exhibited prominent myotonia at rest and muscle fiber-type switching to a more oxidative phenotype compared with controls. Isolated mutant extensor digitorum longus muscles were abnormally sensitive to the Na+/K+ pump inhibitor ouabain and exhibited age-dependent changes, including delayed relaxation and altered generation of tetanic force. Moreover, rapid and sustained weakness of isolated mutant muscles was induced when the extracellular K+ concentration was increased from 4 mM to 10 mM, a level observed in the muscle interstitium of humans during exercise. Mutant muscle ...
Autosomal recessive pseudohypoaldosteronism type 1 (PHA1) is a rare disorder characterized by sodium wasting, failure to thrive, hyperkalemia, hypovolemia and metabolic acidosis. It is due to mutations in the amiloride-sensitive epithelial sodium channel (ENaC) and is characterized by diminished response to aldosterone. Patients may present with life-threatening hyperkalemia, which must be recognized and appropriately treated. A 32-year-old female was referred to the National Institutes of Health (NIH) for evaluation of hyperkalemia and muscle pain. Her condition started in the second week of life, when she was brought to an outside hospital lethargic and unresponsive. At that time, she was hypovolemic, hyperkalemic and acidotic, and was eventually treated with sodium bicarbonate and potassium chelation. At the time of the presentation to the NIH, her laboratory evaluation revealed serum potassium 5.1 mmol/l (reference range: 3.4-5.1 ...
The neuronal voltage-gated sodium channel Nav1.1 encoded by the SCN1A gene plays an important role in the generation and propagation of action potentials in the central nervous system. Altered function of this channel due to mutations in SCN1A leads to hypersynchronous neuronal discharges resulting in seizures or migrainous attaques. A large number of distinct sequence variants in SCN1A are associated with diverse epilepsy and migraine syndromes. We developed an online and freely available database containing all reported sequence variants in SCN1A (http://www.molgen.ua.ac.be/SCN1AMutations/). We verified 623 distinct sequence variants, listed them using standard nomenclature for description and classified them according to their putative pathogenic nature. We provided links to relevant publications and information on the associated phenotype. The database can be queried using cDNA or protein position, ...
INTRODUCTION: Loss-of-function mutations in the SCN5A gene encoding the cardiac sodium channel are responsible for Brugada syndrome (BS) and also for progressive cardiac conduction disease (inherited Lenègre disease). In an attempt to clarify the frontier between these two entities, we have characterized cardiac conduction defect and its evolution with aging in a cohort of 78 patients carrying a SCN5A mutation linked to Brugada syndrome. METHODS AND RESULTS: Families were included in the study if a SCN5A mutation was identified in a BS proband and if at least two family members were mutation carriers. Sixteen families met the study criteria, representing 78 carriers. Resting ECG showed a spontaneous BS ECG pattern in 28 of 78 (36%) gene carriers. Intraventricular conduction anomalies were identified in 59 of 78 gene carriers including complete (17) or incomplete (24) right bundle branch block, right bundle branch block plus hemiblock (6), left bundle branch block (1), ...
Tissue acidosis is effective in causing chronic muscle pain. However, how muscle nociceptors contribute to the transition from acute to chronic pain is largely unknown. Here we showed that a single intramuscular acid injection induced a priming effect on muscle nociceptors of mice. The primed muscle nociceptors were plastic and permitted the development of long-lasting chronic hyperalgesia induced by a second acid insult. The plastic changes of muscle nociceptors were modality-specific and required the activation of acid-sensing ion channel 3 (ASIC3) or transient receptor potential cation channel V1 (TRPV1). Activation of ASIC3 was associated with increased activity of tetrodotoxin (TTX)-sensitive voltage-gated sodium channels but not protein kinase Cϵ (PKCϵ) in isolectin B4 (IB4)-negative muscle nociceptors. In contrast, increased activity of TTX-resistant voltage-gated ...
The no action potential, temperature-sensitive (napts) mutation in Drosophila melanogaster confers resistance to the pyrethroids fenvalerate and permethrin. Additionally we have found that females are more resistant to pyrethroids than males. Piperonyl butoxide can suppress this resistance in a long pyrethroid exposure (,45 min) but has less of an effect during shorter exposures. Since the pyrethroid resistance of napts can be suppressed by piperonyl butoxide, the nap mutant appears to define a phenotypically different locus than the kdr mutant in house flies. Previous work has demonstrated that the napts mutation decreases the number of saxitoxin-binding sodium channels. We propose that the presence of fewer sodium channels in mutant flies delays knockdown by pyrethroids, which act as channel agonists. This delay allows other mechanisms to come into play which, in turn, allow survivial. This model is supported by the ...
Dravet syndrome is a devastating infantile-onset epilepsy syndrome with cognitive deficits and autistic traits caused by genetic alterations in SCN1A gene encoding the α-subunit of the voltage-gated sodium channel Nav1.1. Disease modeling using patient-derived induced pluripotent stem cells (iPSCs) can be a powerful tool to reproduce this syndromes human pathology. However, no such effort has been reported to date. We here report a cellular model for DS that utilizes patient-derived iPSCs. We generated iPSCs from a Dravet syndrome patient with a c.4933C|T substitution in SCN1A, which is predicted to result in truncation in the fourth homologous domain of the protein (p.R1645*). Neurons derived from these iPSCs were primarily GABAergic (|50%), although glutamatergic neurons were observed as a minor population (|1%). Current-clamp analyses revealed significant impairment in action potential generation when strong depolarizing ...
We investigated whether the evolution of electric organs and electric signal diversity in two independently evolved lineages of electric fishes was accompanied by convergent changes on the molecular level. We found that a sodium channel gene (Na(v)1.4a) that is expressed in muscle in nonelectric fishes has lost its expression in muscle and is expressed instead in the evolutionarily novel electric organ in both lineages of electric fishes. This gene appears to be evolving under positive selection in both lineages, facilitated by its restricted expression in the electric organ. This view is reinforced by the lack of evidence for selection on this gene in one electric species in which expression of this gene is retained in muscle. Amino acid replacements occur convergently in domains that influence channel inactivation, a key trait for shaping electric communication signals. Some amino acid replacements occur at or adjacent to sites at which ...
The relative permeability of sodium channels to 21 organic cations was studied in myelinated nerve fibers. Ionic currents under voltage-clamp conditions were measured in sodium-free solutions containing the test cation. The measured reversal potential and the Goldman equation were used to calculate relative permeabilities. The permeability sequence was: sodium ≈ hydroxylamine , hydrazine , ammonium ≈ formamidine ≈ guanidine ≈ hydroxyguanidine , aminoguanididine ,, methylamine. The cations of the following compounds were not measurably permeant: N-methylhydroxylamine, methylhydrazine, methylamine, methylguanidine, acetamidine, dimethylamine, tetramethylammonium, tetraethylammonium, ethanolamine, choline, tris(hydroxymethyl)amino methane, imidazole, biguanide, and triaminoguanidine. Thus methyl and methylene groups render cations impermeant. The results can be explained on geometrical grounds by assuming that the ...
First, we sought to demonstrate a selective knockdown of the NaV1.8 protein. To this end, we created a stable cell line expressing the NaV1.8 protein by transfection followed by G418 selection. Figure 2is an immunocytochemical (A1) and a Western blot (A2) confirmation of the proper expression of NaV1.8 immunoreactive protein of the expected molecular mass (, 260 kd) in the NaV1.8-HEK293 cell line. Infection of this cell line with the shRNA/EGFP-expressing lentivirus resulted in a decrease in the anti-NaV1.8 antibody immunoreactive band detected by a Western blot. As expected, lentivirus only expressing the EGFP reporter or the pan-tetrodotoxin-sensitive shRNA designed to knock down the tetrodotoxin-sensitive α subunits did not inhibit the NaV1.8 protein expression. Of the five shRNA/EGFP constructs targeting the NaV1.8, all demonstrated significant reduction in the immunoreactive protein ...
Surprisingly, mammalian genomes encode only eight to nine independent DEG/ENaC subunits, whereas the genomes of the worm C. elegans and various Drosophila species harbor a significantly larger number of DEG/ENaC-like genes [31 in Drosophila melanogaster and 30 in C. elegans (Bazopoulou et al. 2007; Ben-Shahar 2011; Liu et al. 2003a; Liu et al. 2003b; Studer et al. 2011)]. Consequently, DEG/ENaC genes represent one of the largest ion channel families in the Drosophila genome. The high diversification of DEG/ENaC protein sequences across distant animal species makes it difficult to evaluate whether the family expanded in some invertebrate species or whether it contracted in vertebrates. Nevertheless, the remarkable diversity of ppk genes in Drosophila suggests two alternative hypotheses. The first would suggest DEG/ENaC ion channels serve a wider range of physiological functions relative to their roles in mammals. An alternative hypothesis would be that DEG/ENaC ...
Although survival rates of breast, colon and prostate cancers are improving, deaths from these tumors frequently occur due to metastasis. Voltage-gated Na+ channels (VGSCs) are membrane proteins, which regulate membrane current and cellular migration during nervous system organogenesis. VGSCs are also expressed in fibroblasts, immune cells, glia and metastatic cancer cells. VGSCs regulate migration and invasion of breast, bowel and prostate cancer cells, suggesting that they may be novel anti-metastatic targets. We conducted a systematic review of clinical and preclinical studies testing the effects of VGSC-inhibiting drugs in cancer. 204 publications were identified, of which two human, two mouse and 20 in vitro publications were included. In the clinical studies, the effect of these drugs on survival and metastatic relapse is not clear. The 22 preclinical studies collectively suggest that several VGSC-inhibiting ...
LQT3 mutations in the LQTS Registry will be studied using in vitro expression studies to determine whether ranolazine causes a decrease in late sodium current, slower recovery from inactivation and/or changes in time course of inactivation, ameliorating the causative functional effect of each individual mutation.. Individuals with select LQT3 mutations already studied in vitro will be invited to participate in a short term (2 day) study in the Clinical Research Center studying the effects of an oral dose of ranolazine on QTc duration and other ECG, echocardiogram and Holter-derived parameters.. The same individuals, as well as other individuals with the same mutation, will be invited to participate in a 6-month study involving ranolazine and matched placebo, to help evaluate the long-term effectiveness of ranolazine in the population. Periodic ECGs and 24-hour Holter recordings will be obtained for evaluation of QTc duration and other ECG and Holter-derived parameters. ...
Pyrethroid resistance in human head louse populations is widespread in the United States and worldwide. We previously documented that the knockdown resistance of permethrin-resistant head louse populations is associated with the T929I and L932F (T917I and L920F in the numbering of the louse amino acid sequence) mutations in the voltage-sensitive sodium channel a-subunit gene. In order to identify additional sodium channel mutations potentially associated with knockdown resistance, we cloned and sequenced full-length cDNA fragments from insecticide-susceptible (Ecuador) and permethrin-resistant (Florida) head louse populations and from an insecticide-susceptible body louse population (Israel). Sequence comparisons of the complete open reading frames of the sodium channel genes identified one additional novel mutation (M815I), which was located in the IIS1-2 extracellular loopof the a-subunit, ...
1) Imaging the brain of m igraine sufferers. Flippen C, Welch KMA. Current Opin Neurol 1997;10:226-230.. 2) The periaqueductal grey matter modulates trigeminovascular input: A role in migraine? Knight YE, Goadsby PJ. Neuroscience 2001;106(4):793-800.. 3) Brain stem activation in spontaneous human migraine attacks. Weiller C, May A Limmroth V, et al. Nature Med 1995 Jul;1(7):658-660.. 4) A positron emission tomographic study in spontaneous migraine. Afridi SK, Giffin NJ, Kaube H, Fiston KJ, Ward NS, Frackowiak RS, Goadsby PJ. Arch Neurol 2005; 62(8): 1270-5.. 5) Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca++ channel gene CACNL1A4. Cell 1996;87:543-552.. 6) Mutations in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine type 3. van den Maagdenberg A, Vanmolkot KRJ, Welch KMA, et al. Cephalalgia 2005;25:1189-1205.. 7) Familial basilar migraine associated ...
Ischemia-Related Subcellular Redistribution of Sodium Channels Enhances the Proarrhythmic Effect of Class I Antiarrhythmic Drugs: A Simulation Study. . Biblioteca virtual para leer y descargar libros, documentos, trabajos y tesis universitarias en PDF. Material universiario, documentación y tareas realizadas por universitarios en nuestra biblioteca. Para descargar gratis y para leer online.
Determination of whether bupivacaine enantiomers block Na+ channels differently in the rested, activated, and inactivated channel states may result in a better understanding of their cardiodepressant effects. In the present study, both enantiomers of bupivacaine induced very limited tonic block measured as the reduction of INa amplitude during the first pulse after a long rest period. The amount of block measured from the reduction of peak current reflects both the rested-state block and the activated (open)-state interaction between the Na+ channel and the drug that develops during the depolarizing step before reaching peak current.18 Although tonic block is not necessarily an accurate measure of drug binding to rested Na+ channels, the observed low level indicates that both enantiomers must exhibit a low affinity for the rested state of the Na+ channel. Moreover, the interaction of ...
Redesigning an FKBP-ligand interface to generate chemical dimerizers with novel specificity. Proc Natl Acad Sci U S A (1998) 3.88 The immunophilin FK506-binding protein modulates Ca2+ release channel closure in rat heart. J Physiol (1997) 2.01 Inhibition of human immunodeficiency virus type 1 replication in human cells by Debio-025, a novel cyclophilin binding agent. Antimicrob Agents Chemother (2008) 1.46 Hair growth modulation by topical immunophilin ligands: induction of anagen, inhibition of massive catagen development, and relative protection from chemotherapy-induced alopecia. Am J Pathol (1997) 1.17 Rectification of skeletal muscle ryanodine receptor mediated by FK506 binding protein. Biophys J (1995) 1.10 A role for FKBP52 in Tau protein function. Proc Natl Acad Sci U S A (2010) 1.07 FKBP12 is a critical regulator of the heart rhythm and the cardiac voltage-gated sodium current in mice. Circ Res (2011) 0.99 From nature to the ...
BACKGROUND: Molecular markers of insecticide resistance can provide sensitive indicators of resistance development in malaria vector populations. Monitoring of insecticide resistance in vector populations is an important component of current malaria control programmes. Knockdown resistance (kdr) confers resistance to the pyrethroid class of insecticides with cross-resistance to DDT through single nucleotide polymorphisms (SNPs) in the voltage-gated sodium channel gene. METHODS: To enable detection of kdr mutations at low frequency a method was developed that uses polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA)-based technology, allowing rapid, reliable and cost-effective testing of large numbers of individual mosquitoes. This was used to assay mosquitoes from sites in lower Moshi, Tanzania. RESULTS: Sequence-specific oligonucleotide probes (SSOP) were used for simultaneous detection of both East and West African ...
Collecting duct (CD) renin is stimulated by angiotensin (Ang) II, providing a pathway for Ang I generation and further conversion to Ang II. Ang II stimulates the epithelial sodium channel via the Ang II type 1 receptor and increases mineralocorticoid receptor activity attributed to increased aldosterone release. Our objective was to determine whether CD renin augmentation is mediated directly by Ang II type 1 receptor or via the epithelial sodium channel and mineralocorticoid receptor. In vivo studies examined the effects of epithelial sodium channel blockade (amiloride; 5 mg/kg per day) on CD renin expression and urinary renin content in Ang II-infused rats (80 ng/min, 2 weeks). Ang II infusion increased systolic blood pressure, medullary renin mRNA, urinary renin content, and intrarenal Ang II levels. Amiloride cotreatment did not alter these responses despite a reduction in the rate of progression of ...
Vol 9: Restrictive Expression of Acid-Sensing Ion Channel 5 Asic5 in Unipolar Brush Cells of the Vestibulocerebellum.. . Biblioteca virtual para leer y descargar libros, documentos, trabajos y tesis universitarias en PDF. Material universiario, documentación y tareas realizadas por universitarios en nuestra biblioteca. Para descargar gratis y para leer online.
Using pharmacological screening of a wide spectrum of ion channel antagonists, we found that low concentrations of amiloride inhibited the spiking of water gustatory receptor neurons in Drosophila. Interestingly, several previous studies also demonstrated the effect of amiloride on the spiking of these receptor neurons in the flesh fly and blowfly (Liscia et al., 1997; Sadakata et al., 2002). Using physiological recordings, behavioral assays, and mutational analyses, we identified PPK28 as the putative amiloride-sensitive receptor for gustatory water reception. Further gain-of-function studies showed that PPK28 is sufficient to confer hypoosmotic activity. These results suggest that PPK28 is a good candidate for the Drosophila gustatory water receptor.. The IC50 of amiloride necessary to inhibit the gustatory water response (∼20 μm) was about two orders of magnitude higher than that observed for mammalian ENaC; however, it was comparable to that used for the Drosophila RPK ...
No. Although having low levels of blood potassium during attacks is typical of hypokalemic periodic paralysis, between attacks, people with hypokalemic periodic paralysis can have a normal blood potassium level (frequently in the low normal range). Attacks of paralysis are typically triggered by the level of potassium dropping in the blood. Such potassium fluctuations occur in everyone, but in people with familial hypokalemic periodic paralysis, these drops in potassium can produce episodes of paralysis. For example, a large carbohydrate meal results in secretion of insulin into the blood, which results in a drop of the blood potassium level as potassium and glucose enter cells. In normal people, such a drop in blood potassium produces no symptoms. In people with familial hypokalemic periodic paralysis, however, the drop in blood potassium often triggers an episode of paralysis. Potassium levels in the blood can remain low as muscle is recovering from a recent attack. During an attack, muscles ...
Xenon is developing small molecule inhibitors of the voltage-gated sodium channel Nav1.6 for the treatment of Dravet syndrome. There is a genetic link between
Neurotoxin. Selectively blocks neuronal tetrodotoxin-sensitive voltage-gated sodium channels (Nav) with an IC(50) of 44.6 nM. Does not affect tetrodotoxin-resistant voltage-gated sodium channels or calcium channels.
Manley S.W., Huxham G.J. and Bourke J.R. (1986) Role of sodium influx in thyrotrophin action: Effects of the sodium channel agonist veratridine and thyrotrophin on radioiodine turnover and membrane potential in cultured porcine thyroid cells. Journal of Endocrinology, 110 3: 459-466. ...
TY - JOUR. T1 - Vascular smooth muscle contraction induced by Na+ channel activators, veratridine and batrachotoxin. AU - Shinjo(H), Masayoshi. AU - Toshio, Nakaki. AU - Yukari, Otsuka. AU - Nobuyuki, Sasakawa. AU - Ryuichi, Kato. PY - 1991/11/26. Y1 - 1991/11/26. N2 - The effects of the sodium channel activators veratridine and batrachotoxin on isolated rat aorta were investigated. Veratridine caused gradual contraction, independent of the presence of endolhelium, with an EC50 of 35 μM. Batrachotoxin (1 μM) also induced contraction. Both effects were completely inhibited by the sodium channel blocker tetrodotoxin (1 μM). The veratridine (60 μM)-induced contraction was inhibited by nifedipine (0.1 μM). In the absence of extracellular Ca2+, veratridine (60 μm) did not cause contraction. Sodium nitroprusside (80 nM), acetylcholine (10 μM) and isoproterenol (1 μM) caused relaxation of rings ...
Arterial baroreflex sensitivity is attenuated in chronic heart failure (CHF) state, which is associated with cardiac arrhythmias and sudden cardiac death in patients with CHF. Our previous study showed that CHF-induced sodium channel dysfunction in the baroreceptor neurons was involved in the blunted baroreflex sensitivity in CHF rats. Mitochondria-derived superoxide overproduction decreased expression and activation of the sodium channels in the baroreceptor neurons from CHF rats. However, the molecular mechanisms responsible for the sodium channel dysfunction in the baroreceptor neurons from CHF rats remain unknown. We tested the involvement of nuclear factor κB (NFκB) in the sodium channel dysfunction and evaluated the effects of in vivo transfection of manganese superoxide dismutase gene and NFκB shRNA on the baroreflex function in CHF ...
Looking for online definition of Dravet syndrome in the Medical Dictionary? Dravet syndrome explanation free. What is Dravet syndrome? Meaning of Dravet syndrome medical term. What does Dravet syndrome mean?
Previous studies have reported that enhanced antiarrhythmic effects occur when agents that prolong repolarization are combined with agents that block the sodium channels. The mechanism(s) of this interaction have not been elucidated. In this study, the interactions between the prolongation of action potential duration (APD) by a potassium channel blocker and the reduction in the maximal upstroke velocity of phase 0 of action potential (Vmax) by sodium channel blockers were investigated in guinea pig papillary muscle using conventional microelectrode techniques. Agents that produce selective electrophysiologic effects were chosen, including low concentrations of barium chloride (BaCl2), which selectively blocks the inwardly rectifying potassium current without effects on other repolarizing or depolarizing currents, O-demethyl-encainide (ODME), which blocks the activated sodium ...
Voltage-gated ion channels play fundamental roles in excitable cells, such as neurons, where they enable electric signaling. Normally, this signaling is well controlled, but brain damage, alterations in the ionic composition of the extracellular solution, or dysfunctional ion channels can increase the electrical excitability thereby causing epilepsy. Voltage-gated ion channels are obvious targets for antiepileptic drugs, and, as a rule of thumb, excitability is dampened either by closing voltagegated sodium channels (Nav channels) or by opening voltage-gated potassium channels (Kv channels). For example, several classical antiepileptic drugs block the ion-conducting pore of ...
Previous work has shown that mutation of the gene that encodes the microtubule motor subunit kinesin heavy chain (Khc) in Drosophila inhibits neuronal sodium channel activity, action potentials and neurotransmitter secretion. These physiological defects cause progressive distal paralysis in larvae. To identify the cellular defects that cause these phenotypes, larval nerves were studied by light and electron microscopy. The axons of Khc mutants develop dramatic focal swellings along their lengths. The swellings are packed with fast axonal transport cargoes including vesicles, synaptic membrane proteins, mitochondria and prelysosomal organelles, but not with slow axonal transport cargoes such as cytoskeletal elements. Khc mutations also impair the development of larval motor axon terminals, causing dystrophic morphology and marked reductions in synaptic bouton numbers. These observations suggest that as the concentration of maternally provided wild-type KHC decreases, axonal ...
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Dravet syndrome (DS) is a severe childhood-onset epilepsy commonly due to mutations of the sodium channel gene SCN1A. DS patients have a high risk of sudden unexplained death in epilepsy (SUDEP), believed to be due to cardiac mechanisms. Here we show that DS patients have peri-ictal respiratory dysfunction. One patient who had severe and prolonged postictal hypoventilation later died of SUDEP. Mice with an Scn1aR1407X/+ loss of function mutation died after spontaneous and heat-induced seizures due to central apnea followed by progressive bradycardia. Death could be prevented with mechanical ventilation after seizures induced by hyperthermia or maximal electroshock. Muscarinic receptor antagonists did not prevent bradycardia or death when given at doses selective for peripheral parasympathetic blockade, whereas apnea was prevented at doses known to be high enough to cross the blood brain barrier. Anoxia causes bradycardia due to a direct effect on the heart. We conclude that ...
Dravet syndrome (DS) is a severe childhood-onset epilepsy commonly due to mutations of the sodium channel gene SCN1A. DS patients have a high risk of sudden unexplained death in epilepsy (SUDEP), believed to be due to cardiac mechanisms. Here we show that DS patients have peri-ictal respiratory dysfunction. One patient who had severe and prolonged postictal hypoventilation later died of SUDEP. Mice with an Scn1aR1407X/+ loss of function mutation died after spontaneous and heat-induced seizures due to central apnea followed by progressive bradycardia. Death could be prevented with mechanical ventilation after seizures induced by hyperthermia or maximal electroshock. Muscarinic receptor antagonists did not prevent bradycardia or death when given at doses selective for peripheral parasympathetic blockade, whereas apnea was prevented at doses known to be high enough to cross the blood brain barrier. Anoxia causes bradycardia due to a direct effect on the heart. We conclude that ...
Dravet syndrome (DS) is a severe childhood-onset epilepsy commonly due to mutations of the sodium channel gene SCN1A. DS patients have a high risk of sudden unexplained death in epilepsy (SUDEP), believed to be due to cardiac mechanisms. Here we show that DS patients have peri-ictal respiratory dysfunction. One patient who had severe and prolonged postictal hypoventilation later died of SUDEP. Mice with an Scn1aR1407X/+ loss of function mutation died after spontaneous and heat-induced seizures due to central apnea followed by progressive bradycardia. Death could be prevented with mechanical ventilation after seizures induced by hyperthermia or maximal electroshock. Muscarinic receptor antagonists did not prevent bradycardia or death when given at doses selective for peripheral parasympathetic blockade, whereas apnea was prevented at doses known to be high enough to cross the blood brain barrier. Anoxia causes bradycardia due to a direct effect on the heart. We conclude that ...
Vernakalant was originally developed to target the atrial-specific ultrarapid delayed rectifier K+ current (IKur). However, it is a multichannel blocker inhibiting IKur, the transient outward potassium current (Ito), the peak and late Na currents, the rapidly activating delayed rectifier potassium channels (IKr), and the inward-rectifing potassium channels (IKAch and IKATP). It is now thought that although IKur block may contribute to vernakalants antifibrillatory effect, its most important action is through atrial-selective blockade of the peak sodium current.6 The effective refractory period is made shorter during AF, and lengthening the effective refractory period can lead to AF termination. This can be achieved by prolonging the action potential duration (APD), primarily by inhibiting potassium channels, or by blocking sodium channels, which increases cardiac excitation threshold, slows ...
We found that micromolar concentrations of caffeic acid phenethyl ester blocked voltage-gated sodium channel activity in several invasive cell lines from different cancers, including breast (MDA-MB-231 and MDA-MB-468), colon (SW620) and non-small cell lung cancer (H460). In the MDA-MB-231 cell line, which was adopted as a model, long-term (48h) treatment with 18μM caffeic acid phenethyl ester reduced the peak current density by 91% and shifted steady-state inactivation to more hyperpolarized potentials and slowed recovery from inactivation. The effects of long-term treatment were also dose-dependent, 1μM caffeic acid phenethyl ester reducing current density by only 65%. The effects of caffeic acid phenethyl ester on metastatic cell behaviours were tested on the MDA-MB-231 cell line at a working concentration (1μM) that did not affect proliferative activity. Lateral motility and Matrigel invasion were reduced by up to 14% and 51%, ...
Dravet syndrome (DS) is a severe childhood-onset epilepsy commonly due to mutations of the sodium channel gene SCN1A. DS patients have a high risk of sudden unexplained death in epilepsy (SUDEP), believed to be due to cardiac mechanisms. Here we show that DS patients have peri-ictal respiratory dysfunction. One patient who had severe and prolonged postictal hypoventilation later died of SUDEP. Mice with an Scn1aR1407X/+ loss of function mutation died after spontaneous and heat-induced seizures due to central apnea followed by progressive bradycardia. Death could be prevented with mechanical ventilation after seizures induced by hyperthermia or maximal electroshock. Muscarinic receptor antagonists did not prevent bradycardia or death when given at doses selective for peripheral parasympathetic blockade, whereas apnea was prevented at doses known to be high enough to cross the blood brain barrier. Anoxia causes bradycardia due to a direct effect on the heart. We conclude that ...
Dravet syndrome (DS) is a severe childhood-onset epilepsy commonly due to mutations of the sodium channel gene SCN1A. DS patients have a high risk of sudden unexplained death in epilepsy (SUDEP), believed to be due to cardiac mechanisms. Here we show that DS patients have peri-ictal respiratory dysfunction. One patient who had severe and prolonged postictal hypoventilation later died of SUDEP. Mice with an Scn1aR1407X/+ loss of function mutation died after spontaneous and heat-induced seizures due to central apnea followed by progressive bradycardia. Death could be prevented with mechanical ventilation after seizures induced by hyperthermia or maximal electroshock. Muscarinic receptor antagonists did not prevent bradycardia or death when given at doses selective for peripheral parasympathetic blockade, whereas apnea was prevented at doses known to be high enough to cross the blood brain barrier. Anoxia causes bradycardia due to a direct effect on the heart. We conclude that ...
Dravet syndrome (DS) is a severe childhood-onset epilepsy commonly due to mutations of the sodium channel gene SCN1A. DS patients have a high risk of sudden unexplained death in epilepsy (SUDEP), believed to be due to cardiac mechanisms. Here we show that DS patients have peri-ictal respiratory dysfunction. One patient who had severe and prolonged postictal hypoventilation later died of SUDEP. Mice with an Scn1aR1407X/+ loss of function mutation died after spontaneous and heat-induced seizures due to central apnea followed by progressive bradycardia. Death could be prevented with mechanical ventilation after seizures induced by hyperthermia or maximal electroshock. Muscarinic receptor antagonists did not prevent bradycardia or death when given at doses selective for peripheral parasympathetic blockade, whereas apnea was prevented at doses known to be high enough to cross the blood brain barrier. Anoxia causes bradycardia due to a direct effect on the heart. We conclude that ...
Dravet syndrome (DS) is a severe childhood-onset epilepsy commonly due to mutations of the sodium channel gene SCN1A. DS patients have a high risk of sudden unexplained death in epilepsy (SUDEP), believed to be due to cardiac mechanisms. Here we show that DS patients have peri-ictal respiratory dysfunction. One patient who had severe and prolonged postictal hypoventilation later died of SUDEP. Mice with an Scn1aR1407X/+ loss of function mutation died after spontaneous and heat-induced seizures due to central apnea followed by progressive bradycardia. Death could be prevented with mechanical ventilation after seizures induced by hyperthermia or maximal electroshock. Muscarinic receptor antagonists did not prevent bradycardia or death when given at doses selective for peripheral parasympathetic blockade, whereas apnea was prevented at doses known to be high enough to cross the blood brain barrier. Anoxia causes bradycardia due to a direct effect on the heart. We conclude that ...
Dravet syndrome (DS) is a severe childhood-onset epilepsy commonly due to mutations of the sodium channel gene SCN1A. DS patients have a high risk of sudden unexplained death in epilepsy (SUDEP), believed to be due to cardiac mechanisms. Here we show that DS patients have peri-ictal respiratory dysfunction. One patient who had severe and prolonged postictal hypoventilation later died of SUDEP. Mice with an Scn1aR1407X/+ loss of function mutation died after spontaneous and heat-induced seizures due to central apnea followed by progressive bradycardia. Death could be prevented with mechanical ventilation after seizures induced by hyperthermia or maximal electroshock. Muscarinic receptor antagonists did not prevent bradycardia or death when given at doses selective for peripheral parasympathetic blockade, whereas apnea was prevented at doses known to be high enough to cross the blood brain barrier. Anoxia causes bradycardia due to a direct effect on the heart. We conclude that ...
Dravet syndrome (DS) is a severe childhood-onset epilepsy commonly due to mutations of the sodium channel gene SCN1A. DS patients have a high risk of sudden unexplained death in epilepsy (SUDEP), believed to be due to cardiac mechanisms. Here we show that DS patients have peri-ictal respiratory dysfunction. One patient who had severe and prolonged postictal hypoventilation later died of SUDEP. Mice with an Scn1aR1407X/+ loss of function mutation died after spontaneous and heat-induced seizures due to central apnea followed by progressive bradycardia. Death could be prevented with mechanical ventilation after seizures induced by hyperthermia or maximal electroshock. Muscarinic receptor antagonists did not prevent bradycardia or death when given at doses selective for peripheral parasympathetic blockade, whereas apnea was prevented at doses known to be high enough to cross the blood brain barrier. Anoxia causes bradycardia due to a direct effect on the heart. We conclude that ...
Dravet syndrome (DS) is a severe childhood-onset epilepsy commonly due to mutations of the sodium channel gene SCN1A. DS patients have a high risk of sudden unexplained death in epilepsy (SUDEP), believed to be due to cardiac mechanisms. Here we show that DS patients have peri-ictal respiratory dysfunction. One patient who had severe and prolonged postictal hypoventilation later died of SUDEP. Mice with an Scn1aR1407X/+ loss of function mutation died after spontaneous and heat-induced seizures due to central apnea followed by progressive bradycardia. Death could be prevented with mechanical ventilation after seizures induced by hyperthermia or maximal electroshock. Muscarinic receptor antagonists did not prevent bradycardia or death when given at doses selective for peripheral parasympathetic blockade, whereas apnea was prevented at doses known to be high enough to cross the blood brain barrier. Anoxia causes bradycardia due to a direct effect on the heart. We conclude that ...
Dravet syndrome (DS) is a severe childhood-onset epilepsy commonly due to mutations of the sodium channel gene SCN1A. DS patients have a high risk of sudden unexplained death in epilepsy (SUDEP), believed to be due to cardiac mechanisms. Here we show that DS patients have peri-ictal respiratory dysfunction. One patient who had severe and prolonged postictal hypoventilation later died of SUDEP. Mice with an Scn1aR1407X/+ loss of function mutation died after spontaneous and heat-induced seizures due to central apnea followed by progressive bradycardia. Death could be prevented with mechanical ventilation after seizures induced by hyperthermia or maximal electroshock. Muscarinic receptor antagonists did not prevent bradycardia or death when given at doses selective for peripheral parasympathetic blockade, whereas apnea was prevented at doses known to be high enough to cross the blood brain barrier. Anoxia causes bradycardia due to a direct effect on the heart. We conclude that ...
Thats why a recent paper from Andrew Escaygs lab is so interesting. He studies genes involved in epilepsy. Several years ago, he showed that mice with mutations in the SCN8A gene have absence epilepsy, while also showing resistance to induced seizures. SCN8A is one of those sticks that touches many others. The gene encodes a voltage-gated sodium channel, involved in setting the thresholds for and triggering neurons action potentials. Mutating the gene in mice modifies sleep and even enhances spatial memory.. Escaygs new paper, with first author Jennifer Wong, looks at the effect of "knocking down" SCN8A in the hippocampus in a mouse model of mesial temporal lobe epilepsy. This model doesnt involve sodium channel genes; its generated by injection of a toxin (kainic acid) into the brain. The finding suggests that inhibiting SCN8A may be applicable to other forms of epilepsy. Escayg notes that mesial temporal ...
Topamax (Topiramate) belongs to the group of antiepileptic drugs, which block sodium channels, prevent anxiety and relieve spasms. The medicine is efficient for the treatment of epilepsy, migraine headache and cramps. The drug has spasmolytic, painkilling and anti-inflammatory effect.
authors, ,mainauthor= [[user:Pgpostema,P.G. Postema, MD]] ,supervisor= ,coauthor= [[user:Drj,J.S.S.G. de Jong, MD]] ,moderator= [[user:Pgpostema,P.G. Postema, MD]] ,editor= }} [[Image:Brugada.png,thumb,Typical ECG abnormalities in Brugada syndrome: ST elevation in V1-V3, without ischemia.]] [[Image:Brugada_ecg_characteristics.png,thumb, Typical ECG abnormalities in Brugada syndrome]] [[Image:brugada.jpg,thumb, Dr. Pedro Brugada. Pedro and Josep Brugada described in 1992 a landmark publication with a case-series of 8 patients with sudden cardiac death. ,cite>Brugada,/cite> Currently, three brothers of the Brugada family (Pedro, Josep and Ramon Brugada) conduct research in the syndrome that has been named after them.]] [[Image:scn5a.jpg,thumb, The SCN5a gen is located on the short arm (p) of chromosome 3]] The Brugada syndrome is an hereditary disease that is associated with high risk of sudden cardiac death. It is characterized by typical ECG abnormalities: ST segment elevation in the ...
Permethrin is only found in individuals that have used or taken this drug. It is a pyrethroid insecticide commonly used in the treatment of lice infestations and scabies. It is a yellow to light orange-brown, low melt-ing solid or viscous liquid.Permethrin acts on the nerve cell membrane to disrupt the sodium channel current by which the polarization of the membrane is regulated. Delayed repolarization and paralysis of the pests are the consequences of this disturbance ...
Anti arrhythmic drugs are classified into four main classes. Class I - Sodium channel blockers(act on Phase 0) Class II - Beta blockers(act on phase 4) Class III- Potassium channel blockers(act on phase 3) Class IV - Calcium channel blockers(act …. Read more ». ...
Anti arrhythmic drugs are classified into four main classes.. Class I - Sodium channel blockers(act on Phase 0). Class II - Beta blockers(act on phase 4). Class III- Potassium channel blockers(act on phase 3). Class IV - Calcium channel blockers(act on phase 2). ...
Mutations in a voltage-gated sodium channel (SCN1A) result in Dravet Syndrome (DS), a catastrophic childhood epilepsy. Zebrafish with a mutation in scn1Lab recapitulate salient phenotypes associated with DS including seizures, early fatality and resistance to antiepileptic drugs. To discover new drug candidates for DS, we screened a chemical library of ∼1,000 compounds and identified four compounds that rescued the behavioral seizure component, including one compound (dimethadione) that suppressed associated electrographic seizure activity. Fenfluramine, but not Huperzine A, also showed antiepileptic activity in our zebrafish assays. The effectiveness of compounds that block neuronal calcium current (dimethadione) or enhance serotonin signaling (fenfluramine) in our zebrafish model suggests these may be important therapeutic targets in patients with DS. Over 150 compounds resulting in fatality were also ...
Aconitine (ACO), a highly toxic diterpenoid alkaloid, is recognized to have effects on cardiac voltage-gated Na+ channels. However, it remains unknown whether it has any effects on K+ currents. The effects of ACO on ion currents in differentiated clonal cardiac (H9c2) cells and in cultured neonatal rat ventricular myocytes were investigated in this study. In H9c2 cells, ACO suppressed ultrarapid-delayed rectifier K+ current (IKur) in a time- and concentration-dependent fashion. The IC50 value for ACO-induced inhibition of IKur was 1.4μM. ACO could accelerate the inactivation of IKur with no change in the activation time constant of this current. Steady-state inactivation curve of IKur during exposure to ACO could be demonstrated. Recovery from block by ACO was fitted by a single-exponential function. The inhibition of IKur by ACO could still be observed in H9c2 cells preincubated with ruthenium red (30μM). Intracellular dialysis with ACO ...
Lamictal (Lamotrigine) is a drug that is approved for the treatment of epilepsy and bipolar disorder. It works as a sodium channel blocker by inhibiting vo
Lamictal (Lamotrigine) is a drug that is approved for the treatment of epilepsy and bipolar disorder. It works as a sodium channel blocker by inhibiting vo

Most recent papers with the keyword Sodium channelopathies | Read by QxMDMost recent papers with the keyword Sodium channelopathies | Read by QxMD

Selective voltage-gated sodium channel peptide toxins from animal venom: pharmacological probes and analgesic drug development. ... NaV1.5 contributes to smooth muscle electrical slow waves and mechanical sensitivity. In predominately Caucasian IBS patient ... www.readbyqxmd.com/read/28597987/trafficking-and-localization-to-the-plasma-membrane-of-nav-1-5-promoted-by-the-%C3%AE-2- ... Voltage-gated sodium channels belong to the superfamily of voltage-gated cation channels. Their structure is based on domains ...
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Frontiers | Propranolol Blocks Cardiac and Neuronal Voltage-Gated Sodium Channels | PharmacologyFrontiers | Propranolol Blocks Cardiac and Neuronal Voltage-Gated Sodium Channels | Pharmacology

Voltage-gated sodium channels are established pharmacological targets for local anesthetics and many other drugs with shared ... These data indicate that brain sodium channels exhibit less sensitivity to R-(+)-propranolol than NaV1.5 channels. Based upon ... Figure 8. Biophysical effects of lidocaine on NaV1. 5-F1760A channels. (A) Current-voltage relationships in the absence and ... and both drugs can block voltage-gated sodium channels. Moreover, propranolol has been shown to have anti-convulsive properties ...
more infohttps://www.frontiersin.org/articles/10.3389/fphar.2010.00144/full

CK2-An Emerging Target for Neurological and Psychiatric DisordersCK2-An Emerging Target for Neurological and Psychiatric Disorders

CK2 was further found to directly phosphorylate the voltage gated sodium channel NAv1, thereby enhancing its binding to ankyrin ... channels are gated by the Ca2+ sensor calmodulin. Phosphorylation of calmodulin by CK2 reduces its Ca2+ sensitivity and leads ... Drugs that can diffuse through the BBB must be of small molecular size (less than 500 Da), highly lipophilic, and not ionized ... CK2 activity is required for the interaction of FGF14 with voltage-gated sodium channels and neuronal excitability. FASEB J. ...
more infohttp://pubmedcentralcanada.ca/pmcc/articles/PMC5374411/

Marine Drugs  | Free Full-Text | µ-Conotoxins Modulating Sodium Currents in Pain Perception and Transmission: A Therapeutic...Marine Drugs | Free Full-Text | µ-Conotoxins Modulating Sodium Currents in Pain Perception and Transmission: A Therapeutic...

µ and µO-CTX are two isoforms that specifically target voltage-gated sodium channels. These, by inducing the entrance of sodium ... In this review, we describe the current knowledge of µ-CTX interacting with the different sodium channels subtypes, the ... Hyperexcitability and mutations of sodium channels are responsible for perception and transmission of inflammatory and ... Mahdavi, S.; Kuyucak, S. Molecular dynamics study of binding of µ-conotoxin GIIIA to the voltage-gated sodium channel Nav1. 4. ...
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Gastrin-Releasing Peptide-Preferring ReceptorsGastrin-Releasing Peptide-Preferring Receptors

Loss-of-function mutations in the gene encoding voltage-gated sodium route Nav1. Nav1.7-null January 21, 2019. Published by: ... whereas the 4-subunit of voltage-gated calcium mineral channels has been proven to truly have a part like a transcription ... JUPITER is an initial prevention trial of people without prior coronary disease or diabetes but with raised high-sensitivity C- ... Rheumatologists know about this, and display individuals for sepsis before you start the drugs, specifically tuberculosis,4,5 ...
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Interacting with the environment receiving and interpreting signals - PDF Free DownloadInteracting with the environment receiving and interpreting signals - PDF Free Download

transient receptor potential a cation channel with 30 transmembrane domains voltage gated sodium channel voltage gated calcium ... This finding led them to conclude that SCN9A sodium channel was essential for pain sensitivity. Key genes and channels ... noted that many pain syndromes are due to defect in activity of Nav1 type channels caused by mutations in sodium channel genes ... exposure to ototoxic drugs. In a few cases genetic defects were postulated to cause this disorder. They noted that development ...
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Most recent papers with the keyword Drug induced paroxysmal movement disorders | Read by QxMDMost recent papers with the keyword Drug induced paroxysmal movement disorders | Read by QxMD

... cases linked to gain-of-function mutations in SCN9A which encodes voltage-gated sodium channel Nav1.7. Severe pain episodes and ... Startle syndromes are paroxysmal and show stimulus sensitivity, placing them in the differential diagnosis of epileptic ... https://www.readbyqxmd.com/read/18803825/paroxysmal-extreme-pain-disorder-m1627k-mutation-in-human-nav1-7-renders-drg-neurons- ... The pathophysiology of PKC is uncertain but it could be an ion-channel disorder. Antiepileptic drugs particularly carbamazepine ...
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Voltage-gated sodium channels (VGSCs) contain a pore-forming -subunit and regulatory -subunits.. 14 May 2019 ovarian ... 1. Coexpression with -subunits considerably affected enough time span of fast inactivation aswell as the voltage sensitivities ... Clones for rat 1 and 2 (Nav1 and Nav2), supplied by Prof. Alan Goldin (College or university of California, Irvine, CA), in ... Background There happens to be simply no anti-fibrotic drug therapy open ...
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Neosaxitoxin - WikipediaNeosaxitoxin - Wikipedia

"Blockers of Voltage-Gated Sodium Channels for the Treatment of Central Nervous System Diseases". Recent Patents on CNS Drug ... Invertebrates possess two Nav channels (Nav1 and Nav2), whereas vertebrate Nav channels are of the Nav1 family. Sodium-channel ... Vornanen M, Hassinen M, Haverinen J (2011). "Tetrodotoxin sensitivity of the vertebrate cardiac Na+ current". Marine Drugs. 9 ( ... "Voltage gated", also called "voltage sensitive" and "voltage dependant" sodium channel also known as "VGSCs" or "Nav channel" ...
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JCI -
A disease mutation reveals a role for NaV1.9 in acute itchJCI - A disease mutation reveals a role for NaV1.9 in acute itch

The voltage-gated sodium channel Na(v)1.9 is an effector of peripheral inflammatory pain hypersensitivity. J Neurosci. 2006;26( ... Compared with other NaV channel subtypes, the expression patterns, functional properties, and pharmacological sensitivities of ... Ho TW, Backonja M, Ma J, Leibensperger H, Froman S, Polydefkis M. Efficient assessment of neuropathic pain drugs in patients ... Functional analysis of stably expressed human Nav1. Biophys J. 2012;102:527a. ...
more infohttps://omoyshop.net.insight.mobile.jci.org/articles/view/122481

Frontiers | Novel Computational Approach to Predict Off-Target Interactions for Small Molecules | Big DataFrontiers | Novel Computational Approach to Predict Off-Target Interactions for Small Molecules | Big Data

The OTSA process correctly identified the known pharmacological targets for , 70% of these drugs, but also predicted a ... Undesired off-target interactions are often not detected using current drug discovery assays, such as experimental poly- ... Of these, 3923 and 4067 possible high-scoring interactions were predicted for the discontinued and approved drugs, respectively ... Undesired off-target interactions are often not detected using current drug discovery assays, such as experimental ...
more infohttps://www.frontiersin.org/articles/10.3389/fdata.2019.00025/full

monocytes | p53 modulates acquired resistance to EGFR inhibitorsmonocytes | p53 modulates acquired resistance to EGFR inhibitors

Intro gene encodes the -subunit of cardiac voltage-gated Na+ channels (Nav1.5), which generate the inward sodium current (INa) ... Introduction We functionally analyzed a frameshift mutation in the gene encoding cardiac Na+ channels (Nav1. that was not ... recommending that PKA gates LTP by preventing/or contending with proteins phosphatases (find below). The calcium-sensitivity ... Many drugs that target transforming growth factor- (TGF) signalling have disease. Posted by Terrence Collins on December 4, ...
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Application # 2012/0010207. Chemical Compounds - Patents.comApplication # 2012/0010207. Chemical Compounds - Patents.com

0003] Voltage-gated sodium channels are found in all excitable cells including myocytes of muscle and neurons of the central ... In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, ... increased sensitivity to a noxious stimulus) and allodynia (sensitivity to a normally innocuous stimulus). [0165] The ... The Nav1.x subfamily can be functionally subdivided into two groups, those which are sensitive to blocking by tetrodotoxin (TTX ...
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Voltage-gated Na+ currents in human dorsal root ganglion neurons | eLifeVoltage-gated Na+ currents in human dorsal root ganglion neurons | eLife

Human sensory neurons may not only bridge a critical gap between drug discovery and clinical trials, but force a re-evaluation ... "ProTx-I and ProTx-II inhibit all sodium channel (Nav1) subtypes tested with similar potency." (Priest et al. Toxicon. 2007 49: ... They show that this protocol works in the absence of drugs, but obviously it may not in the presence of drugs that can modify ... that the TTX-S current is likely to be primarily from Nav1.7 channels based on its sensitivity to PF-05089771, but that it is ( ...
more infohttps://elifesciences.org/articles/23235

APP processing in Alzheimers disease | Molecular Brain | Full TextAPP processing in Alzheimer's disease | Molecular Brain | Full Text

... including the voltage-gated sodium channel (Nav1) β2 subunit, Golgi-localized membrane-bound α2,6-sialyltransferase, P-selectin ... Marcade M, Bourdin J, Loiseau N, Peillon H, Rayer A, Drouin D, Schweighoffer F, Desire L: Etazolate, a neuroprotective drug ... of peripheral nerves and had altered neurological behaviors such as reduced grip strength and elevated pain sensitivity, likely ... and had subtle electrophysiological alterations in the steady-state inactivation of their voltage-gated sodium channels. They ...
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ChannelpediaChannelpedia

All L-type voltage gated Ca channels are characterized by high sensitivity to dihydropyridine (DHP) Ca2+ channel modulators, ... and antiarrhythmic drugs bind to overlapping receptor sites located in the inner cavity of the pore of the sodium channel [815] ... KCNE channel alters KCNQ5 channel gating. The proteins KCNE1 and KCNE3 alter the gating of the Kv7.5 channel in Xenopus oocytes ... CAP-1A binds to a conserved motif present in NaV1.8 linking voltage-gated sodium channels to clathrin, which is involved in ...
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Combinatorial augmentation of voltage-gated KCNQ potassium channels by chemical openers. Proc. Natl. Acad. Sci. U.S.A., 2008 ... Sodium and potassium channel dysfunctions in rare and common idiopathic epilepsy syndromes. Brain Dev., 2009 Aug , 31 (515-20). ... The effects of the drugs were stronger on KCNQ2 than on KCNQ3 channel alpha subunits but they did not enhance KCNQ1 K(+) ... Neuronal M-current exhibited a similar sensitivity. I.e. extracellular H+ ions affected two distinct properties of KCNQ2/3 ...
more infohttps://channelpedia.epfl.ch/ionchannels/24

Activity-induced Ca2+ signaling in perisynaptic Schwann cells of the early postnatal mouse is mediated by P2Y1 receptors and...Activity-induced Ca2+ signaling in perisynaptic Schwann cells of the early postnatal mouse is mediated by P2Y1 receptors and...

... inactivating Nav1.4 voltage-gated sodium channels at the NMJ, and consequently blocking the production of muscle action ... Drugs were either bath applied in proximity to the motor endplate or pressure injected (PDES-O2DX; NPI Electronic). Drugs ... For example, the sensitivity of Nav1.4, which is expressed at high levels in a restricted region in the depths of the ... Accumulation of Nav1 mRNAs at differentiating postsynaptic sites in rat soleus muscles * MA Stocksley ...
more infohttps://elifesciences.org/articles/30839

Publications | neuro.ulaval.caPublications | neuro.ulaval.ca

Regulation of Cardiac Voltage-Gated Sodium Channel by Kinases: Roles of Protein Kinases A and C. Handb Exp Pharmacol. 2017;. * ... Biophysical characterization of the Varroa destructor NaV1 sodium channel and its affinity for τ-fluvalinate insecticide. FASEB ... High Sensitivity Mapping of Cortical Dopamine D2 Receptor Expressing Neurons. Cereb Cortex. 2018;. *PubMed ... Current and Promising Therapies in Autosomal Recessive Ataxias. CNS Neurol Disord Drug Targets. 2018;17(3):161-171. *PubMed ...
more infohttps://neuro.ulaval.ca/fr/publications

1 - Types of Binary Option signals Silver1 - Types of Binary Option signals Silver

Therefore, the voltage across each of the four resistors is simply Va, Vb. The more complex the data structures, the more ... People often have to try 2 or 3 impotence drugs before they find a treatment that works.. SexDrugsAndHouse. Very amusing ... Jensen R, Brinck T, Olesen J (1994) Sodium Valproate has a Prophylactic Effect in Migraine without Aura: A Triple-Blind, ... and mutations in the gene for this protein result in the specific loss of touch-sensitivity with no apparent defect in other ...
more infohttp://demo.binaryinternationalreviews.com/types-of-binary-option-signals-silver.html

ChannelpediaChannelpedia

voltage-gated potassium channel complex. A protein complex that forms a transmembrane channel through which potassium ions may ... Inactivation of the sodium channel. I. Sodium current experiments. J. Gen. Physiol., 1977 Nov , 70 (549-66). ... Pharmacological sensitivity of the mKv1.7 channel were performed, IC50 values in each case being determined when block reached ... Anti-arythmic drugs. amiodarone (Kd=35±muM), flecainide (Kd=8±muM) and quinidine (Kd=15±2 muM). all block kv1.7 [387] ...
more infohttps://channelpedia.epfl.ch/ionchannels/7

PonstanPonstan

... suggest that fenamates may influence neuronal excitability through modulation of ligand and/or voltage-gated ion channels. In ... Sodium (1) sodium benzoate (9) sodium butyrate (4) Sodium Potassium Pump (1) Somalia (1) Sonic (1) Sotos (2) Soy (1) SPAK (3) ... Epigenetics (1) DNM (1) Donepzil (3) Dopamine (2) Double-tap (1) Down Syndrome (12) Dravet Syndrome (3) drug (4) DS (2) DSM (2) ... This increased Ca2+ sensitivity is dependent on the specific type of β subunit associating with the BK channel [106, 107]. In ...
more infohttps://epiphanyasd.blogspot.com/search/label/Ponstan

ExcitotoxicityExcitotoxicity

Point mutations in the gene encoding the L-type voltage-gated channels Ca v1.2 (CACNA1C) and Ca v1.4. (CACNA1F) prevent voltage ... Sodium (1) sodium benzoate (8) sodium butyrate (4) Sodium Potassium Pump (1) Somalia (1) Sonic (1) Sotos (2) Soy (1) SPAK (3) ... Epigenetics (1) DNM (1) Donepzil (3) Dopamine (2) Double-tap (1) Down Syndrome (12) Dravet Syndrome (3) drug (4) DS (2) DSM (2) ... Nav1 (1) Nav1.1 (4) Nav1.3 (1) Nav1.4 (1) Naviaux (2) Nazi (1) NCIMB 30242 (1) NCIMB 30350 (1) NCIMB 30351 (1) NCSA (1) NDAE (1 ...
more infohttps://epiphanyasd.blogspot.com/search/label/Excitotoxicity

Epiphany: January 2015Epiphany: January 2015

The accepted method of action is that working as a voltage gate sodium channel blocker. GABA is not mentioned.. ... Epigenetics (1) DNM (1) Donepzil (3) Dopamine (2) Double-tap (1) Down Syndrome (12) Dravet Syndrome (3) drug (4) DS (2) DSM (2) ... Nav1 (1) Nav1.1 (4) Nav1.3 (1) Nav1.4 (1) Naviaux (2) Nazi (1) NCIMB 30242 (1) NCIMB 30350 (1) NCIMB 30351 (1) NCSA (1) NDAE (1 ... So if the trial had ended at week 6 we would conclude that cinnamon does not increase insulin sensitivity.. ...
more infohttps://epiphanyasd.blogspot.com/2015/01/

Molecular Dissection of Calmodulin Domain Functions - Madeline SheaMolecular Dissection of Calmodulin Domain Functions - Madeline Shea

Channelopathies associated with the voltage-dependent sodium channel family (d... ... Calcium-regulated ion channels control essential processes in nerves and muscles. ... Human voltage-gated sodium channels in the NaV family are regulated by calmodulin (CaM) and responsible for the rising phase of ... Channelopathies associated with the voltage-dependent sodium channel family (denoted NaV1.n, VDSC or VGSC) include several ...
more infohttp://grantome.com/grant/NIH/R01-GM057001-10
  • Investigators from the University of British Columbia, Great Ormond Street Hospital for Children, and the National Hospital reported their findings on neurotransmitter deficiencies in two patients with mutations in voltage-gated sodium genes (SCN2A and SCN8A) discovered by whole exome sequencing. (readbyqxmd.com)
  • In this study examined a racially and ethnically diverse cohort of IBS patients for SCN5A missense mutations, and compared them to IBS negative controls, and determined the resulting NaV1. (readbyqxmd.com)
  • Hyperexcitability and mutations of sodium channels are responsible for perception and transmission of inflammatory and neuropathic pain states. (mdpi.com)
  • Furthermore, loss-of-function Nav1.5 mutations have already been described in sufferers with idiopathic ventricular fibrillation (IVF), an uncommon and lethal condition which occurs as syncope or sudden cardiac loss of life in teenagers with normal hearts and without electrophysiological manifestations of inherited arrhythmogenic syndromes [5- (boothampitheatre.com)
  • Interestingly, unlike additional C-terminal website truncating mutations , the mutation here presented did not modify INa,L suggesting that deletions of different lengths can differentially impact gating properties of the variants. (boothampitheatre.com)
  • Several mutations truncate the channel before or in the A domain or the putative assembly domain, shown as beige and white boxes respectively. (epfl.ch)
  • Calmodulin bound to KCNQ2 acts as a Ca2+ sensor, conferring Ca2+ dependence to the trafficking of the channel to the plasma membrane. (epfl.ch)
  • Here, we report a new clinical case of debilitating itch and altered pain perception resulting from the heterozygous de novo p.L811P gain-of-function mutation in Na V 1.9, a voltage-gated sodium (Na V ) channel subtype that relays sensory information from the periphery to the spine. (jci.org)
  • Recent evidence has demonstrated the significant roles of Nav subtypes (Nav1.3, 1.7, 1.8 and 1.9) in nociceptive transduction and therefore these Navs may represent attractive targets for analgesic drug discovery. (readbyqxmd.com)
  • In this review, we describe the current knowledge of µ-CTX interacting with the different sodium channels subtypes, the mechanism of action and their potential therapeutic use as analgesic compounds in the clinical management of pain conditions. (mdpi.com)
  • Undesired off-target interactions are often not detected using current drug discovery assays, such as experimental polypharmacological screens. (frontiersin.org)
  • Of these, 3,923 and 4,067 possible high-scoring interactions were predicted for the discontinued and approved drugs, respectively, translating to an average of 9.3 interactions per drug. (frontiersin.org)
  • About 51.5% (2,025) and 22% (900) of these predicted high-scoring interactions have not previously been reported for the discontinued and approved drugs, respectively, and these may have a potential for repurposing efforts. (frontiersin.org)
  • The clone for rat NaV1.8, supplied by Prof. John Timber Rabbit Polyclonal to EPHA3/4/5 (phospho-Tyr779/833) (College or university University, London, UK) in pRK7, was linearized with HpaI. (ovarian-cancersymptoms.com)
  • 2008). Each oocyte was injected with 69 nl of NaV1.8 cRNA without buy 82586-52-5 or with -subunit cRNA (35 ng of every). (ovarian-cancersymptoms.com)
  • Former five, but more recently, six neurotoxin receptor sites have been recognized between the seven receptor site located in the vertebrate sodium channel receptor alpha subunit: Site 1 binds the sodium channel blockers tetrodotoxin and saxitoxin. (wikipedia.org)
  • Our results indicate that while the two major current types, generally referred to as tetrodotoxin (TTX)-sensitive and TTX-resistant were qualitatively similar in neurons from rats and humans, there were several differences that have important implications for drug development as well as our understanding of pain mechanisms. (elifesciences.org)
  • If the external loops of the BKB1- and BKB4-subunits are exchanged (chimeras b1Lb4 and b4Lb1), the phenotypes obtained regarding toxin binding correspond to their respective loops (e.g., chimera b1Lb4 has a toxin sensitivity corresponding to the BKB4 subunit). (epfl.ch)
  • In fact, in rat cerebellar Purkinje neurons there are multiple endogenous protein kinases and phosphatases that functionally couple to the BK channel modulating their activity. (epfl.ch)
  • Voltage-gated sodium (Na(+)) channels are expressed in virtually all electrically excitable tissues and are essential for muscle contraction and the conduction of impulses within the peripheral and central nervous systems. (readbyqxmd.com)
  • Earlier in vitro electrophysiological studies of the effects of propranolol on heart rate and conduction performed in frog atria, rat and canine ventricular myocytes suggested that the drug might be interacting with sodium channels. (frontiersin.org)
  • Because of their importance to the conduction of electrical signals, Na(+) channels are the target of a wide variety of local anesthetic, antiarrhythmic, anticonvulsant, and antidepressant drugs. (readbyqxmd.com)
  • Additionally, the computed physiochemical properties such as clogP (i.e., lipophilicity), molecular weight, pKa and logS (i.e., solubility) were found to be statistically different between the approved and discontinued drugs, but the internal compounds were close to the approved drugs space in most part. (frontiersin.org)
  • Meclofenamic acid (meclofenamate) and diclofenac, two related molecules previously used as anti-inflammatory drugs, act as KCNQ2/Q3 channel openers. (epfl.ch)
  • Mepyramine and diphenhydramine, two structurally related first-generation antihistamines, can act as potent KCNQ/M channel blockers. (epfl.ch)
  • Such models integrate experimental data, assist in planning new experiments, and may facilitate drug design. (readbyqxmd.com)
  • The voltage and metal sensors all control the opening of the same ionic pore in response to various physiological signals . (epfl.ch)
  • Furthermore, C-terminal website bears several regions critical for protein-protein connection, particularly the PDZ binding website, which, in turn, are critical for channel trafficking and surface manifestation. (boothampitheatre.com)
  • More particularly the invention relates to a new sulfonamide Nav1.7 inhibitors of formula (I): ##STR00001## or a pharmaceutically acceptable salt thereof, wherein Ar.sup.1, X, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined in the description. (patents.com)