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, Inwardly Rectifying: Potassium channels where the flow of K+ ions into the cell is greater than the outward flow.Sulfonylurea Receptors: ATP-BINDING CASSETTE PROTEINS that are highly conserved and widely expressed in nature. They form an integral part of the ATP-sensitive potassium channel complex which has two intracellular nucleotide folds that bind to sulfonylureas and their analogs.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.Glyburide: An antidiabetic sulfonylurea derivative with actions similar to those of chlorpropamide.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.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.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.Receptors, Drug: Proteins that bind specific drugs with high affinity and trigger intracellular changes influencing the behavior of cells. Drug receptors are generally thought to be receptors for some endogenous substance not otherwise specified.Decanoic Acids: 10-carbon saturated monocarboxylic acids.Hydroxy Acids: Organic compounds containing both the hydroxyl and carboxyl radicals.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.Adenosine 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.Cromakalim: A potassium-channel opening vasodilator that has been investigated in the management of hypertension. It has also been tried in patients with asthma. (Martindale, The Extra Pharmacopoeia, 30th ed, p352)Diazoxide: A benzothiadiazine derivative that is a peripheral vasodilator used for hypertensive emergencies. It lacks diuretic effect, apparently because it lacks a sulfonamide group.Pinacidil: A guanidine that opens POTASSIUM CHANNELS producing direct peripheral vasodilatation of the ARTERIOLES. It reduces BLOOD PRESSURE and peripheral resistance and produces fluid retention. (Martindale The Extra Pharmacopoeia, 31st ed)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.Calcium Channel Blockers: A class of drugs that act by selective inhibition of calcium influx through cellular membranes.Tolbutamide: A sulphonylurea hypoglycemic agent with actions and uses similar to those of CHLORPROPAMIDE. (From Martindale, The Extra Pharmacopoeia, 30th ed, p290)Chloride Channels: Cell membrane glycoproteins that form channels to selectively pass chloride ions. Nonselective blockers include FENAMATES; ETHACRYNIC ACID; and TAMOXIFEN.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.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.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.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.Sulfonylurea CompoundsMembrane 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).Potassium Channels, Calcium-Activated: Potassium channels whose activation is dependent on intracellular calcium concentrations.Sarcolemma: The excitable plasma membrane of a muscle cell. (Glick, Glossary of Biochemistry and Molecular Biology, 1990)Ischemic Preconditioning, Myocardial: Exposure of myocardial tissue to brief, repeated periods of vascular occlusion in order to render the myocardium resistant to the deleterious effects of ISCHEMIA or REPERFUSION. The period of pre-exposure and the number of times the tissue is exposed to ischemia and reperfusion vary, the average being 3 to 5 minutes.Benzopyrans: Compounds with a core of fused benzo-pyran rings.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.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.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.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).Electric Conductivity: The ability of a substrate to allow the passage of ELECTRONS.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.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.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.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.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.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.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.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.Nicorandil: A derivative of the NIACINAMIDE that is structurally combined with an organic nitrate. It is a potassium-channel opener that causes vasodilatation of arterioles and large coronary arteries. Its nitrate-like properties produce venous vasodilation through stimulation of guanylate cyclase.Vasodilator Agents: Drugs used to cause dilation of the blood vessels.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.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.Kv1.3 Potassium Channel: A delayed rectifier subtype of shaker potassium channels that is the predominant VOLTAGE-GATED POTASSIUM CHANNEL of T-LYMPHOCYTES.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.Kv1.2 Potassium Channel: A delayed rectifier subtype of shaker potassium channels that is selectively inhibited by a variety of SCORPION VENOMS.Kv1.1 Potassium Channel: A delayed rectifier subtype of shaker potassium channels that is commonly mutated in human episodic ATAXIA and MYOKYMIA.Hypoglycemic Agents: Substances which lower blood glucose levels.Guanidines: A family of iminourea derivatives. The parent compound has been isolated from mushrooms, corn germ, rice hulls, mussels, earthworms, and turnip juice. Derivatives may have antiviral and antifungal properties.Adenosine Diphosphate: Adenosine 5'-(trihydrogen diphosphate). An adenine nucleotide containing two phosphate groups esterified to the sugar moiety at the 5'-position.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.Xenopus: An aquatic genus of the family, Pipidae, occurring in Africa and distinguished by having black horny claws on three inner hind toes.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.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.Dose-Response Relationship, Drug: The relationship between the dose of an administered drug and the response of the organism to the drug.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.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.Congenital Hyperinsulinism: A familial, nontransient HYPOGLYCEMIA with defects in negative feedback of GLUCOSE-regulated INSULIN release. Clinical phenotypes include HYPOGLYCEMIA; HYPERINSULINEMIA; SEIZURES; COMA; and often large BIRTH WEIGHT. Several sub-types exist with the most common, type 1, associated with mutations on an ATP-BINDING CASSETTE TRANSPORTERS (subfamily C, member 8).Islets of Langerhans: Irregular microscopic structures consisting of cords of endocrine cells that are scattered throughout the PANCREAS among the exocrine acini. Each islet is surrounded by connective tissue fibers and penetrated by a network of capillaries. There are four major cell types. The most abundant beta cells (50-80%) secrete INSULIN. Alpha cells (5-20%) secrete GLUCAGON. PP cells (10-35%) secrete PANCREATIC POLYPEPTIDE. Delta cells (~5%) secrete SOMATOSTATIN.Kinetics: The rate dynamics in chemical or physical systems.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.Mitochondria, Heart: The mitochondria of the myocardium.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.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.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.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.KCNQ1 Potassium Channel: A voltage-gated potassium channel that is expressed primarily in the HEART.Action Potentials: Abrupt changes in the membrane potential that sweep along the CELL MEMBRANE of excitable cells in response to excitation stimuli.Cell Line: Established cell cultures that have the potential to propagate indefinitely.Cell Membrane: The lipid- and protein-containing, selectively permeable membrane that surrounds the cytoplasm in prokaryotic and eukaryotic cells.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.Gliclazide: An oral sulfonylurea hypoglycemic agent which stimulates insulin secretion.Adamantane: A tricyclo bridged hydrocarbon.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.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.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.Kv1.4 Potassium Channel: A fast inactivating subtype of shaker potassium channels that contains two inactivation domains at its N terminus.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.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.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.Dihydropyridines: Pyridine moieties which are partially saturated by the addition of two hydrogen atoms in any position.Shaw Potassium Channels: A shaker subfamily that is prominently expressed in NEURONS and are necessary for high-frequency, repetitive firing of ACTION POTENTIALS.Myocytes, Cardiac: Striated muscle cells found in the heart. They are derived from cardiac myoblasts (MYOBLASTS, CARDIAC).Minoxidil: A potent direct-acting peripheral vasodilator (VASODILATOR AGENTS) that reduces peripheral resistance and produces a fall in BLOOD PRESSURE. (From Martindale, The Extra Pharmacopoeia, 30th ed, p371)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.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.Thiamylal: A barbiturate that is administered intravenously for the production of complete anesthesia of short duration, for the induction of general anesthesia, or for inducing a hypnotic state. (From Martindale, The Extra Pharmacopoeia, 30th ed, p919)Muscle, Smooth, Vascular: The nonstriated involuntary muscle tissue of blood vessels.Vasodilation: The physiological widening of BLOOD VESSELS by relaxing the underlying VASCULAR SMOOTH MUSCLE.Sodium: A member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23.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.Rana esculenta: An edible species of the family Ranidae, occurring in Europe and used extensively in biomedical research. Commonly referred to as "edible frog".Magnesium: A metallic element that has the atomic symbol Mg, atomic number 12, and atomic weight 24.31. It is important for the activity of many enzymes, especially those involved in OXIDATIVE PHOSPHORYLATION.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.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.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.Heart Ventricles: The lower right and left chambers of the heart. The right ventricle pumps venous BLOOD into the LUNGS and the left ventricle pumps oxygenated blood into the systemic arterial circulation.Heart: The hollow, muscular organ that maintains the circulation of the blood.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.Calcium Channels, P-Type: CALCIUM CHANNELS located within the PURKINJE CELLS of the cerebellum. They are involved in stimulation-secretion coupling of neurons.COS Cells: CELL LINES derived from the CV-1 cell line by transformation with a replication origin defective mutant of SV40 VIRUS, which codes for wild type large T antigen (ANTIGENS, POLYOMAVIRUS TRANSFORMING). They are used for transfection and cloning. (The CV-1 cell line was derived from the kidney of an adult male African green monkey (CERCOPITHECUS AETHIOPS).)Pyrroles: Azoles of one NITROGEN and two double bonds that have aromatic chemical properties.Receptors, Purinergic P1: A class of cell surface receptors that prefer ADENOSINE to other endogenous PURINES. Purinergic P1 receptors are widespread in the body including the cardiovascular, respiratory, immune, and nervous systems. There are at least two pharmacologically distinguishable types (A1 and A2, or Ri and Ra).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.Adenosine: A nucleoside that is composed of ADENINE and D-RIBOSE. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter.Myocardial Ischemia: A disorder of cardiac function caused by insufficient blood flow to the muscle tissue of the heart. The decreased blood flow may be due to narrowing of the coronary arteries (CORONARY ARTERY DISEASE), to obstruction by a thrombus (CORONARY THROMBOSIS), or less commonly, to diffuse narrowing of arterioles and other small vessels within the heart. Severe interruption of the blood supply to the myocardial tissue may result in necrosis of cardiac muscle (MYOCARDIAL INFARCTION).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.Benzylidene Compounds: Compounds containing the PhCH= radical.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.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.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)Intermediate-Conductance Calcium-Activated Potassium Channels: A major class of calcium-activated potassium channels that were originally discovered in ERYTHROCYTES. They are found primarily in non-excitable CELLS and set up electrical gradients for PASSIVE ION TRANSPORT.Time Factors: Elements of limited time intervals, contributing to particular results or situations.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.Insulinoma: A benign tumor of the PANCREATIC BETA CELLS. Insulinoma secretes excess INSULIN resulting in HYPOGLYCEMIA.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.Purinergic P1 Receptor Agonists: Compounds that bind to and stimulate PURINERGIC P1 RECEPTORS.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.Calcium Channels, Q-Type: CALCIUM CHANNELS located in the neurons of the brain.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.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.Myocardial Reperfusion Injury: Damage to the MYOCARDIUM resulting from MYOCARDIAL REPERFUSION (restoration of blood flow to ischemic areas of the HEART.) Reperfusion takes place when there is spontaneous thrombolysis, THROMBOLYTIC THERAPY, collateral flow from other coronary vascular beds, or reversal of vasospasm.Delayed Rectifier Potassium Channels: A group of slow opening and closing voltage-gated potassium channels. Because of their delayed activation kinetics they play an important role in controlling ACTION POTENTIAL duration.Insulin: A 51-amino acid pancreatic hormone that plays a major role in the regulation of glucose metabolism, directly by suppressing endogenous glucose production (GLYCOGENOLYSIS; GLUCONEOGENESIS) and indirectly by suppressing GLUCAGON secretion and LIPOLYSIS. Native insulin is a globular protein comprised of a zinc-coordinated hexamer. Each insulin monomer containing two chains, A (21 residues) and B (30 residues), linked by two disulfide bonds. Insulin is used as a drug to control insulin-dependent diabetes mellitus (DIABETES MELLITUS, TYPE 1).Diacetyl: Carrier of aroma of butter, vinegar, coffee, and other foods.Calcium Channels, R-Type: CALCIUM CHANNELS located in the neurons of the brain. They are inhibited by the marine snail toxin, omega conotoxin MVIIC.Ischemic Preconditioning: A technique in which tissue is rendered resistant to the deleterious effects of prolonged ISCHEMIA and REPERFUSION by prior exposure to brief, repeated periods of vascular occlusion. (Am J Physiol 1995 May;268(5 Pt 2):H2063-7, Abstract)Binding Sites: The parts of a macromolecule that directly participate in its specific combination with another molecule.2,4-Dinitrophenol: A toxic dye, chemically related to trinitrophenol (picric acid), used in biochemical studies of oxidative processes where it uncouples oxidative phosphorylation. It is also used as a metabolic stimulant. (Stedman, 26th ed)Tetraethylammonium: A potassium-selective ion channel blocker. (From J Gen Phys 1994;104(1):173-90)Models, Molecular: Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures.Charybdotoxin: A 37-amino acid residue peptide isolated from the scorpion Leiurus quinquestriatus hebraeus. It is a neurotoxin that inhibits calcium activated potassium channels.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.Glucose: A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement.Cricetinae: A subfamily in the family MURIDAE, comprising the hamsters. Four of the more common genera are Cricetus, CRICETULUS; MESOCRICETUS; and PHODOPUS.Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors.Nucleotides: The monomeric units from which DNA or RNA polymers are constructed. They consist of a purine or pyrimidine base, a pentose sugar, and a phosphate group. (From King & Stansfield, A Dictionary of Genetics, 4th ed)Electric Stimulation: Use of electric potential or currents to elicit biological responses.Anesthetics, Inhalation: Gases or volatile liquids that vary in the rate at which they induce anesthesia; potency; the degree of circulation, respiratory, or neuromuscular depression they produce; and analgesic effects. Inhalation anesthetics have advantages over intravenous agents in that the depth of anesthesia can be changed rapidly by altering the inhaled concentration. Because of their rapid elimination, any postoperative respiratory depression is of relatively short duration. (From AMA Drug Evaluations Annual, 1994, p173)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.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.Sodium Cyanide: A highly poisonous compound that is an inhibitor of many metabolic processes and is used as a test reagent for the function of chemoreceptors. It is also used in many industrial processes.8,11,14-Eicosatrienoic Acid: A 20-carbon-chain fatty acid, unsaturated at positions 8, 11, and 14. It differs from arachidonic acid, 5,8,11,14-eicosatetraenoic acid, only at position 5.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)Rubidium Radioisotopes: Unstable isotopes of rubidium that decay or disintegrate emitting radiation. Rb atoms with atomic weights 79-84, and 86-95 are radioactive rubidium isotopes.Sodium Azide: A cytochrome oxidase inhibitor which is a nitridizing agent and an inhibitor of terminal oxidation. (From Merck Index, 12th ed)Recombinant Proteins: Proteins prepared by recombinant DNA technology.Cyclic AMP-Dependent Protein Kinases: A group of enzymes that are dependent on CYCLIC AMP and catalyze the phosphorylation of SERINE or THREONINE residues on proteins. Included under this category are two cyclic-AMP-dependent protein kinase subtypes, each of which is defined by its subunit composition.Voltage-Dependent Anion Channels: A family of voltage-gated eukaryotic porins that form aqueous channels. They play an essential role in mitochondrial CELL MEMBRANE PERMEABILITY, are often regulated by BCL-2 PROTO-ONCOGENE PROTEINS, and have been implicated in APOPTOSIS.Cyclic GMP: Guanosine cyclic 3',5'-(hydrogen phosphate). A guanine nucleotide containing one phosphate group which is esterified to the sugar moiety in both the 3'- and 5'-positions. It is a cellular regulatory agent and has been described as a second messenger. Its levels increase in response to a variety of hormones, including acetylcholine, insulin, and oxytocin and it has been found to activate specific protein kinases. (From Merck Index, 11th ed)Lipid Bilayers: Layers of lipid molecules which are two molecules thick. Bilayer systems are frequently studied as models of biological membranes.PhenanthridinesDogs: The domestic dog, Canis familiaris, comprising about 400 breeds, of the carnivore family CANIDAE. They are worldwide in distribution and live in association with people. (Walker's Mammals of the World, 5th ed, p1065)Anoxia: Relatively complete absence of oxygen in one or more tissues.Insulin-Secreting Cells: A type of pancreatic cell representing about 50-80% of the islet cells. Beta cells secrete INSULIN.Protein Kinase C: An serine-threonine protein kinase that requires the presence of physiological concentrations of CALCIUM and membrane PHOSPHOLIPIDS. The additional presence of DIACYLGLYCEROLS markedly increases its sensitivity to both calcium and phospholipids. The sensitivity of the enzyme can also be increased by PHORBOL ESTERS and it is believed that protein kinase C is the receptor protein of tumor-promoting phorbol esters.Nifedipine: A potent vasodilator agent with calcium antagonistic action. It is a useful anti-anginal agent that also lowers blood pressure.Membrane Transport Modulators: Agents that affect ION PUMPS; ION CHANNELS; ABC TRANSPORTERS; and other MEMBRANE TRANSPORT PROTEINS.Cations: Positively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis.Benzophenanthridines: Compounds of four rings containing a nitrogen. They are biosynthesized from reticuline via rearrangement of scoulerine. They are similar to BENZYLISOQUINOLINES. Members include chelerythrine and sanguinarine.Isoflurane: A stable, non-explosive inhalation anesthetic, relatively free from significant side effects.Nitric Oxide: A free radical gas produced endogenously by a variety of mammalian cells, synthesized from ARGININE by NITRIC OXIDE SYNTHASE. Nitric oxide is one of the ENDOTHELIUM-DEPENDENT RELAXING FACTORS released by the vascular endothelium and mediates VASODILATION. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic GUANYLATE CYCLASE and thus elevates intracellular levels of CYCLIC GMP.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.Nitroprusside: A powerful vasodilator used in emergencies to lower blood pressure or to improve cardiac function. It is also an indicator for free sulfhydryl groups in proteins.Animals, Newborn: Refers to animals in the period of time just after birth.Pyridines: Compounds with a six membered aromatic ring containing NITROGEN. The saturated version is PIPERIDINES.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.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.Hydrogen Sulfide: A flammable, poisonous gas with a characteristic odor of rotten eggs. It is used in the manufacture of chemicals, in metallurgy, and as an analytical reagent. (From Merck Index, 11th ed)Chlorides: Inorganic compounds derived from hydrochloric acid that contain the Cl- ion.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.PyransCoronary Circulation: The circulation of blood through the CORONARY VESSELS of the HEART.Biophysics: The study of PHYSICAL PHENOMENA and PHYSICAL PROCESSES as applied to living things.Calcium Gluconate: The calcium salt of gluconic acid. The compound has a variety of uses, including its use as a calcium replenisher in hypocalcemic states.HEK293 Cells: A cell line generated from human embryonic kidney cells that were transformed with human adenovirus type 5.Gramicidin: A group of peptide antibiotics from BACILLUS brevis. Gramicidin C or S is a cyclic, ten-amino acid polypeptide and gramicidins A, B, D are linear. Gramicidin is one of the two principal components of TYROTHRICIN.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.Pia Mater: The innermost layer of the three meninges covering the brain and spinal cord. It is the fine vascular membrane that lies under the ARACHNOID and the DURA MATER.Mutagenesis, Site-Directed: Genetically engineered MUTAGENESIS at a specific site in the DNA molecule that introduces a base substitution, or an insertion or deletion.Sodium Channel Agonists: A class of drugs that stimulate sodium influx through cell membrane channels.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.Mice, Knockout: Strains of mice in which certain GENES of their GENOMES have been disrupted, or "knocked-out". To produce knockouts, using RECOMBINANT DNA technology, the normal DNA sequence of the gene being studied is altered to prevent synthesis of a normal gene product. Cloned cells in which this DNA alteration is successful are then injected into mouse EMBRYOS to produce chimeric mice. The chimeric mice are then bred to yield a strain in which all the cells of the mouse contain the disrupted gene. Knockout mice are used as EXPERIMENTAL ANIMAL MODELS for diseases (DISEASE MODELS, ANIMAL) and to clarify the functions of the genes.Cell Hypoxia: A condition of decreased oxygen content at the cellular level.4-Aminopyridine: One of the POTASSIUM CHANNEL BLOCKERS, with secondary effect on calcium currents, which is used mainly as a research tool and to characterize channel subtypes.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.Apamin: A highly neurotoxic polypeptide from the venom of the honey bee (Apis mellifera). It consists of 18 amino acids with two disulfide bridges and causes hyperexcitability resulting in convulsions and respiratory paralysis.Coronary Vessels: The veins and arteries of the HEART.omega-Conotoxin GVIA: A neurotoxic peptide, which is a cleavage product (VIa) of the omega-Conotoxin precursor protein contained in venom from the marine snail, CONUS geographus. It is an antagonist of CALCIUM CHANNELS, N-TYPE.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.Cyclic AMP: An adenine nucleotide containing one phosphate group which is esterified to both the 3'- and 5'-positions of the sugar moiety. It is a second messenger and a key intracellular regulator, functioning as a mediator of activity for a number of hormones, including epinephrine, glucagon, and ACTH.Mesenteric Arteries: Arteries which arise from the abdominal aorta and distribute to most of the intestines.Biophysical Phenomena: The physical characteristics and processes of biological systems.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).Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as CATIONS; those with a negative charge are ANIONS.Syntaxin 1: A neuronal cell membrane protein that combines with SNAP-25 and SYNAPTOBREVIN 2 to form a SNARE complex that leads to EXOCYTOSIS.Cardiotonic Agents: Agents that have a strengthening effect on the heart or that can increase cardiac output. They may be CARDIAC GLYCOSIDES; SYMPATHOMIMETICS; or other drugs. They are used after MYOCARDIAL INFARCT; CARDIAC SURGICAL PROCEDURES; in SHOCK; or in congestive heart failure (HEART FAILURE).
Two regions of sulfonylurea receptor specify the spontaneous bursting and ATP inhibition of KATP channel isoforms. (1/595)
KATP channels are heteromultimers of KIR6.2 and a sulfonylurea receptor, SUR, an ATP binding cassette (ABC) protein with several isoforms. KIR6.2 forms a channel pore whose spontaneous activity and ATP sensitivity are modulated by the receptor via an unknown interaction(s). Side by side comparison of single-channel kinetics and steady-state ATP inhibition of human beta-cell, SUR1/KIR6.2, versus cardiac, SUR2A/KIR6.2 channels demonstrate that the latter have a greater mean burst duration and open probability in the absence of nucleotides and approximately 4-fold higher IC50(ATP). We have used matched chimeras of SUR1 and SUR2A to show that the kinetics, which determine the maximal open probability (Pomax), and the ATP sensitivity are functionally separable and to identify the two segments of SUR responsible for these isoform differences. A region within the first five transmembrane domains specifies the interburst kinetics, whereas a C-terminal segment determines the sensitivity to inhibitory ATP. The separable effects of SUR on ATP inhibition and channel kinetics implies that the cytoplasmic C terminus of SUR either directly modulates the affinity of a weak ATP binding site on the inward rectifier or affects linkage between the binding site and the gate. This is the first identification of parts of an ABC protein that interact with an ion channel subunit to modulate the spontaneous activity and ATP sensitivity of the heteromeric channel. (+info)ATP-Sensitive K+ channel modulator binding to sulfonylurea receptors SUR2A and SUR2B: opposite effects of MgADP. (2/595)
KATP channels are heteromeric complexes of inwardly rectifying K+ channel subunits and sulfonylurea receptors (SURs). SUR2A and SUR2B, which differ within the carboxyl terminal exon 38, are characteristic for the cardiac and smooth muscle type channels, respectively. Here we compare binding of the tritiated KATP channel opener, [3H]P1075, to membranes from human embryonic kidney (HEK) cells transfected with murine SUR2A and 2B at 37 degrees C. Binding to both SURs required addition of Mg2+ and ATP in the low micromolar range. In the presence of MgATP, micromolar concentrations of MgADP, formed by the ATPase activity of the membrane preparation, increased binding to SUR2A but inhibited binding to SUR2B. Decreasing temperatures strongly reduced [3H]P1075 binding to SUR2A, whereas binding to SUR2B was increased in a bell-shaped manner. Kinetic experiments revealed a faster dissociation of the [3H]P1075-SUR2A complex, whereas the association rate constants for [3H]P1075 binding to SUR2A and 2B were similar. Openers inhibited [3H]P1075 binding to SUR2A with potencies approximately 4 times lower than to SUR2B; in contrast, glibenclamide inhibited [3H]P1075 binding to SUR2A approximately 8 times more potently than to SUR2B. The data suggest that SUR2A and 2B represent the opener receptors of cardiac and vascular smooth muscle KATP channels, respectively, and show that MgADP is an important modulator of opener binding to SUR. The different carboxyl termini of SUR2A and 2B lead to differences in the MgADP dependence and the thermodynamics of [3H]P1075 binding, as well as in the affinities for openers and glibenclamide, underlining the importance of this part of the molecule for KATP channel modulator binding. (+info)Sulfonylurea and K(+)-channel opener sensitivity of K(ATP) channels. Functional coupling of Kir6.2 and SUR1 subunits. (3/595)
The sensitivity of K(ATP) channels to high-affinity block by sulfonylureas and to stimulation by K(+) channel openers and MgADP (PCOs) is conferred by the regulatory sulfonylurea receptor (SUR) subunit, whereas ATP inhibits the channel through interaction with the inward rectifier (Kir6.2) subunit. Phosphatidylinositol 4, 5-bisphosphate (PIP(2)) profoundly antagonized ATP inhibition of K(ATP) channels expressed from cloned Kir6.2+SUR1 subunits, but also abolished high affinity tolbutamide sensitivity. By stabilizing the open state of the channel, PIP(2) drives the channel away from closed state(s) that are preferentially affected by high affinity tolbutamide binding, thereby producing an apparent loss of high affinity tolbutamide inhibition. Mutant K(ATP) channels (Kir6. 2[DeltaN30] or Kir6.2[L164A], coexpressed with SUR1) also displayed an "uncoupled" phenotype with no high affinity tolbutamide block and with intrinsically higher open state stability. Conversely, Kir6. 2[R176A]+SUR1 channels, which have an intrinsically lower open state stability, displayed a greater high affinity fraction of tolbutamide block. In addition to antagonizing high-affinity block by tolbutamide, PIP(2) also altered the stimulatory action of the PCOs, diazoxide and MgADP. With time after PIP(2) application, PCO stimulation first increased, and then subsequently decreased, probably reflecting a common pathway for activation of the channel by stimulatory PCOs and PIP(2). The net effect of increasing open state stability, either by PIP(2) or mutagenesis, is an apparent "uncoupling" of the Kir6.2 subunit from the regulatory input of SUR1, an action that can be partially reversed by screening negative charges on the membrane with poly-L-lysine. (+info)Phosphoinositides decrease ATP sensitivity of the cardiac ATP-sensitive K(+) channel. A molecular probe for the mechanism of ATP-sensitive inhibition. (4/595)
Anionic phospholipids modulate the activity of inwardly rectifying potassium channels (Fan, Z., and J.C. Makielski. 1997. J. Biol. Chem. 272:5388-5395). The effect of phosphoinositides on adenosine triphosphate (ATP) inhibition of ATP-sensitive potassium channel (K(ATP)) currents was investigated using the inside-out patch clamp technique in cardiac myocytes and in COS-1 cells in which the cardiac isoform of the sulfonylurea receptor, SUR2, was coexpressed with the inwardly rectifying channel Kir6.2. Phosphoinositides (1 mg/ml) increased the open probability of K(ATP) in low [ATP] (1 microM) within 30 s. Phosphoinositides desensitized ATP inhibition with a longer onset period (>3 min), activating channels inhibited by ATP (1 mM). Phosphoinositides treatment for 10 min shifted the half-inhibitory [ATP] (K(i)) from 35 microM to 16 mM. At the single-channel level, increased [ATP] caused a shorter mean open time and a longer mean closed time. Phosphoinositides prolonged the mean open time, shortened the mean closed time, and weakened the [ATP] dependence of these parameters resulting in a higher open probability at any given [ATP]. The apparent rate constants for ATP binding were estimated to be 0.8 and 0.02 mM(-1) ms(-1) before and after 5-min treatment with phosphoinositides, which corresponds to a K(i) of 35 microM and 5.8 mM, respectively. Phosphoinositides failed to desensitize adenosine inhibition of K(ATP). In the presence of SUR2, phosphoinositides attenuated MgATP antagonism of ATP inhibition. Kir6.2DeltaC35, a truncated Kir6.2 that functions without SUR2, also exhibited phosphoinositide desensitization of ATP inhibition. These data suggest that (a) phosphoinositides strongly compete with ATP at a binding site residing on Kir6.2; (b) electrostatic interaction is a characteristic property of this competition; and (c) in conjunction with SUR2, phosphoinositides render additional, complex effects on ATP inhibition. We propose a model of the ATP binding site involving positively charged residues on the COOH-terminus of Kir6.2, with which phosphoinositides interact to desensitize ATP inhibition. (+info)Role of ATP-dependent K(+) channels in the electrical excitability of early embryonic stem cell-derived cardiomyocytes. (5/595)
Single, murine embryonic stem cell-derived early stage cardiomyocytes dissociated from embryoid bodies expressed two inward rectifier K(+) channels, I(K1) and the ATP dependent K(+) current. I(K1) exhibited low density in early stage cardiomyocytes, but increased significantly in late stage cells. In contrast, the ATP dependent K(+) current was expressed at similar densities in early and late stage cardiomyocytes. This current was found to be involved in the determination of the membrane potential, since glibenclamide depolarized early cardiomyocytes and exerted a positive chronotropic effect. Some cardiomyocytes displayed a bursting behavior of action potentials, characterized by alternating periods with and without action potentials. During the phases without action potentials, the membrane potential was hyperpolarized, indicating the involvement of K(+) channels in the generation of this bursting behavior. Extracellular recording techniques were applied to spontaneously contracting areas of whole embryoid bodies. In 20% of these bursting behavior similar to that seen in the single cells was observed. In regularly beating embryoid bodies, bursting could be induced by reduction of substrates from the extracellular medium as well as by superfusion with the positive chronotropic agents Bay K 8644 or isoproterenol. Perfusion with substrate-reduced medium induced bursting behavior after a short latency, isoproterenol and Bay K 8644 resulted in a positive chronotropic response followed by bursting behavior with longer latencies. The spontaneous bursting was blocked by glibenclamide. These experimental results suggest that intermittent activation of ATP dependent K(+) channels underlies the bursting behavior observed in single cardiomyocytes and in the whole embryoid body. Conditions of metabolic stress lead to the rhythmic suppression of action potential generation. Our data indicate that ATP dependent K(+) channels play a prominent role in the cellular excitability of early cardiomyocytes. (+info)KATP channels and 'border zone' arrhythmias: role of the repolarization dispersion between normal and ischaemic ventricular regions. (6/595)
1. In order to investigate the role of KATP channel activation and repolarization dispersion on the 'border zone' arrhythmias induced by ischaemia-reperfusion, the effects of glibenclamide and bimakalim, agents modifying action potential (AP) duration, were studied in an in vitro model of myocardial 'border zone'. 2. The electrophysiological effects of 10 microM glibenclamide and 1 microM bimakalim (n=8 each), respectively KATP channel blocker and activator, were investigated on guinea-pig ventricular strips submitted partly to normal conditions (normal zone, NZ) and partly to simulated ischaemic then reperfused conditions (altered zone, AZ). 3. By preventing the ischaemia-induced AP shortening (P<0.0001), glibenclamide reduced the dispersion of AP duration 90% (APD90) between NZ and AZ (P<0.0001), and concomitantly inhibited the 'border zone' arrhythmias induced by an extrastimulus (ES), their absence being significantly related to the lessened APD90 dispersion (chi2=8.28, P<0.01). 4. Bimakalim, which also reduced the APD90 dispersion (P<0.005) due to differential AP shortening in normal and ischaemic tissues, decreased the incidence of myocardial conduction blocks (25% of preparations versus 83% in control, n=12, P<0.05) and favoured 'border zone' spontaneous arrhythmias (75% of preparations versus 25% in control, P<0.05). 5. During reperfusion, unlike bimakalim, glibenclamide inhibited the ES-induced arrhythmias and reduced the incidence of the spontaneous ones (12% of preparations versus 92% in control, P<0.05), this latter effect being significantly related (chi2=6.13, P<0.02) to the lessened ischaemia-induced AP shortening in the presence of glibenclamide (P<0.0001). 6. These results suggest that KATP blockade may protect the ischaemic-reperfused myocardium from 'border zone' arrhythmias concomitantly with a reduction of APD90 dispersion between normal and ischaemic regions. Conversely, KATP channel activation may modify the incidence of conduction blocks and exacerbate the ischaemia-induced 'border zone' arrhythmias. (+info)Activation of Ca(2+)-dependent K(+) channels contributes to rhythmic firing of action potentials in mouse pancreatic beta cells. (7/595)
We have applied the perforated patch whole-cell technique to beta cells within intact pancreatic islets to identify the current underlying the glucose-induced rhythmic firing of action potentials. Trains of depolarizations (to simulate glucose-induced electrical activity) resulted in the gradual (time constant: 2.3 s) development of a small (<0.8 nS) K(+) conductance. The current was dependent on Ca(2+) influx but unaffected by apamin and charybdotoxin, two blockers of Ca(2+)-activated K(+) channels, and was insensitive to tolbutamide (a blocker of ATP-regulated K(+) channels) but partially (>60%) blocked by high (10-20 mM) concentrations of tetraethylammonium. Upon cessation of electrical stimulation, the current deactivated exponentially with a time constant of 6.5 s. This is similar to the interval between two successive bursts of action potentials. We propose that this Ca(2+)-activated K(+) current plays an important role in the generation of oscillatory electrical activity in the beta cell. (+info)(+)-[3H]isradipine and [3H]glyburide bindings to heart and lung membranes from rats with monocrotaline-induced pulmonary hypertension. (8/595)
We examined the binding of a 1,4-dihydropyridine-sensitive Ca2+ channel ligand, (+)-[3H]isradipine (PN200-110), and that of an ATP-sensitive K+ (K(ATP)) channel ligand, [3H]glyburide, to heart, lung and brain membranes isolated from Sprague-Dawley rats made pulmonary hypertensive by monocrotaline, a pyrrolizidine alkaloid. A single subcutaneous injection of monocrotaline increased right ventricular systolic pressure, a measure of pulmonary arterial pressure, and the thickness of the right ventricular free wall in 3 to 4 weeks. The (+)-[3H]PN200-110 and [3H]glyburide binding site densities (Bmax) were reduced in hypertrophied right ventricles when normalized per unit protein in comparison with those of age-matched control (sham) rats, whereas the values of the dissociation constant (Kd) of both ligands bound to the hypertrophied right ventricle were not significantly changed. The [3H]PN200-110 binding to the lung membranes of the monocrotaline-induced pulmonary hypertensive rats was increased. The results indicate that the change in the binding of 1,4-dihydropyridine Ca2+ and K(ATP) channel ligands to heart membranes may contribute to the pathological alteration of cardiopulmonary structure and functions in rats with pulmonary hypertension induced by monocrotaline. (+info)
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Regulation of KATP Channel Trafficking in Pancreatic β Cells by Protein Histidine Phosphorylation | Diabetes
Hypertrophy decreases cardiac KATP channel responsiveness to exogenous and locally generated (glycolytic) ATP.
Stimulation of neuronal KATP channels by cGMP-dependent protein kinase: involvement of ROS and 5-hydroxydecanoate-sensitive...
The ATP-sensitive potassium (KATP) channel-encoded dSUR gene is required for Drosophila heart function and is regulated by...
Defective trafficking and function of KATP channels caused by a sulfonylurea receptor 1 mutation associated with persistent...
KATP - ATP-sensitive potassium channels | AcronymAttic
Muscle Dysfunction Caused by a KATP Channel Mutation in Neonatal Diabetes Is Neuronal in Origin | Science
WO1998029545 NOVEL SEQUENCES OF p56 PROTEINS WHICH AFFECT K-ATP CHANNELS
KATP Channel May Be Inhibited by Sulfonylureas; Increasing Stroke Risk - MPR
KATP channel mutation confers risk for vein of Marshall adrenergic atrial fibrillation
KCNJ11 gene knockout of the Kir6.2 KATP channel causes maladaptive remodeling and heart failure in hypertension
Vulnerability of the Retinal Microvasculature to Hypoxia: Role of Polyamine-Regulated KATP Channels | IOVS | ARVO Journals
Abstract 193: Regulation of Mitochondrial KATP Channels In Pressure Overloaded Mouse Hearts | Circulation Research
Fenofibrate, Troglitazone, and 15-Deoxy-Δ12,14-prostaglandin J2 Close KATP Channels and Induce Insulin Secretion | Journal of...
Dextromethorphan and dextrorphan influence insulin secretion by interacting with KATP and L-type Ca2+ channels in pancreatic β...
Opening of Mitochondrial KATP Channels Attenuates the Ouabain-Induced Calcium Overload in Mitochondria | Circulation Research
Anti-diabetic drug binding site in a mammalian KATP channel revealed by Cryo-EM | eLife
The role of the vascular KATP channel in septic models - UCL Discovery
KATP channel subunits in rat dorsal root ganglia: alterations by painful axotomy | Springer for Research & Development
PDB-6baa: Cryo-EM structure of the pancreatic beta-cell KATP channel bound ... - Yorodumi
Kinetic Analysis of the Inhibitory Effect of Glibenclamide on KATP Channels of Mammalian Skeletal Muscle, The Journal of...
SUR1SarcolemmalSubunitElectrophysiologyCurrentsSubunitsIschemicProtectivePancreatic beta-cellsInhibitionVascularActivitySuggestShowEffectsPotassium channelSecretionKir6.2GlibenclamideDiazoxideSulfonylurea receptorKir6.1IntracellularRegulationReceptorsLoss of KATP channel activityPlasma membrane KATP channelsMutationsActivationIschemiaActivate KATP channelsMutationAdenosine TriphosphatePancreatic beta-cellInward rectifierMembrane potentialMetabolicSUR2BPharmacologicalPathwayBlockerDiabetesOpenersKineticsMolecularOxidative stressAntagonistDecreasesHumansGlucoseCardiac myocytesMitochondrial ATP-sensitivePhysiologyBlockadeMouse pancreatic beta cellsFunctionalGenesInducesGeneReceptorMiceRegulateInhibitsSensitivityInhibitory effect
SUR12
- The beta-cell K-ATP channel consists of a pore-forming subunit, Kir6.2, and a regulatory subunit, SUR1. (ox.ac.uk)
- The site at which ATP mediates channel inhibition lies on Kir6.2, while the potentiatory action of MgADP involves the nucleotide-binding domains of SUR1. (ox.ac.uk)
Sarcolemmal1
- It has been previously shown that the level of SUR2A mRNA correlates well with the number of fully assembled sarcolemmal KATP channels and that this parameter could be used as a proxy measurement of the level of sarcolemmal KATP channels [19, 26- (nih.gov)
Subunit1
- In mice, the Coxsackievirus B3 replicates to higher titers in the hearts of mayday mutant animals, which are deficient in the Kir6.1 subunit of K(ATP) channels, than in controls. (scripps.edu)
Electrophysiology1
- As nicotinamide has a similar structure as a KATP channels opener nicorandil, we have tested whether nicotinamide would have any direct effect on KATP channels activity by using perforated patch clamp electrophysiology. (nih.gov)
Currents1
- Activation and inhibition of K-ATP currents by guanine nucleotides is mediated by different channel subunits. (ox.ac.uk)
Subunits3
- It is not known, however, whether guanine nucleotides mediate their effects by direct interaction with one or more of the K-ATP channel subunits or indirectly via a GTP-binding protein. (ox.ac.uk)
- Expression of KATP channel subunits in hearts of mice on control and nicotinamide-rich diet. (nih.gov)
- We have analysed levels of SUR2A mRNA as well as mRNAs of two other KATP channel subunits, Kir6.2 and Kir6.1, in mice fed with control and nicotinamide-rich diet. (nih.gov)
Ischemic1
- Soon after the onset of ischemia, the activation of K ATP channels decreases vascular resistance and increases blood flow (ischemic vasodilation) and renders myocardial cells more resistant to a subsequent bout of ischemia (the so-called ischemic preconditioning) ( 8 , 9 ). (diabetesjournals.org)
Protective2
- K ATP channels are also abundantly present in the cardiac muscle and in vascular smooth muscle cells in coronary and peripheral arteries, where they play a key role in the protective mechanisms that are triggered during ischemia ( 6 , 7 ). (diabetesjournals.org)
- A great deal of experimental evidence shows that glibenclamide and the other sulfonylurea compounds, which are not β-cell-specific, block cardiovascular K ATP channels and prevent both protective phenomena ( 8 - 11 ). (diabetesjournals.org)
Pancreatic beta-cells1
- The ATP-sensitive potassium channel (K-ATP channel) plays a key role in insulin secretion from pancreatic beta-cells. (ox.ac.uk)
Inhibition1
- The evidence of poor outcome in diabetic patients undergoing percutaneous coronary angioplasty for acute myocardial infarction while taking sulfonylureas is consistent with the hypothesis that long-term inhibition of K ATP channels may impair myocardial tolerance to severe ischemia ( 18 ). (diabetesjournals.org)
Vascular1
- OBJECTIVE -Sulfonylureas block the activation of vascular potassium-dependent ATP channels and impair the vasodilating response to ischemia in nondiabetic individuals, but it is not known whether this occurs in type 2 diabetic patients under chronic treatment with these drugs. (diabetesjournals.org)
Activity2
- Metabolic regulation is mediated by changes in ATP and MgADP concentration, which inhibit and potentiate channel activity, respectively. (ox.ac.uk)
- The effect of K(ATP) channels is dependent on the RNA interference genes Dcr-2, AGO2, and r2d2, indicating that an activity associated with this potassium channel participates in this antiviral pathway in Drosophila. (scripps.edu)
Suggest1
- Together, our data suggest that K(ATP) channel deregulation can have a critical impact on innate antiviral immunity in the heart. (scripps.edu)
Show1
- Here, we show that in Drosophila ATP-sensitive potassium channels (K(ATP)) mediate resistance to a cardiotropic RNA virus, Flock House virus (FHV). (scripps.edu)
Effects1
- A physiological basis explaining the potentially detrimental effects of sulfonylureas has been provided by the discovery that sulfonylurea drugs stimulate insulin secretion by blocking β-cell ATP-sensitive K + (K ATP ) channels ( 5 ). (diabetesjournals.org)
Potassium channel29
- The ATP-sensitive potassium channel (K ATP ) regulates insulin secretion in pancreatic β cells. (pnas.org)
- Patients bearing these mutations also have poor responses to diazoxide, a potassium channel opener commonly used to treat PHHI, because the same mutations cause parallel decreases in channel response to diazoxide ( 15 , 16 ). (pnas.org)
- An ATP-sensitive potassium channel (or K ATP channel) is a type of potassium channel that is gated by intracellular nucleotides, ATP and ADP. (acronymattic.com)
- They are formed as a functional complex of two unrelated subunits-a member of the Kir inward rectifier potassium channel family, and a sulfonylurea receptor (SUR), a member of the ATP-binding cassette transporter family, which includes cystic fibrosis transmembrane conductance regulators and multidrug resistance protein, regulators of chloride channel activity. (rupress.org)
- In these pancreatic cells, a membrane protein called ATP sensitive potassium channel, K ATP channel for short, acts as a switch that turns on and off the production of insulin. (elifesciences.org)
- The ATP-sensitive potassium channel (K-ATP channel) plays a key role in insulin secretion from pancreatic beta-cells. (ox.ac.uk)
- The ATP-sensitive potassium channel (KATP) was discovered in 1983. (ebook.de)
- In particular, mRNA levels of the inwardly rectifying potassium channel Kir6.1 and the sulfonylurea receptor 2B, which together form the vascular smooth muscle ATP-sensitive potassium channel, were both up-regulated by GH treatment and highly correlated to systolic blood pressure. (bioscientifica.com)
- Increased expression of the ATP-sensitive potassium channel, recently shown to be crucial in the regulation of vascular tone, constitutes a possible mechanism by which GH governs vascular tone. (bioscientifica.com)
- The effect of K(ATP) channels is dependent on the RNA interference genes Dcr-2, AGO2, and r2d2, indicating that an activity associated with this potassium channel participates in this antiviral pathway in Drosophila. (scripps.edu)
- These allow for nucleotide-mediated regulation of the potassium channel, and are critical in its roles as a sensor of metabolic status. (wikipedia.org)
- The KCNJ5 gene provides instructions for making a protein that functions as a potassium channel, which means that it transports positively charged atoms (ions) of potassium (K + ) into and out of cells. (medlineplus.gov)
- KCNJ5 gene mutations associated with this condition change single protein building blocks (amino acids) in the potassium channel. (medlineplus.gov)
- To determine therapeutic plasma levels, plasma half-life and pharmacokinetics of exendin-(9-39) during an intravenous short-term infusion in subjects with congenital hyperinsulinism due to Adenosine triphosphate (ATP)-sensitive potassium channel (KATP) mutations. (clinicaltrials.gov)
- Objective: Animal and human myocytes demonstrate significant swelling and reduced contractility during exposure to stress (metabolic inhibition, hyposmotic stress, or hyperkalemic cardioplegia), and these detrimental consequences may be inhibited by the addition of diazoxide (adenosine triphosphate-sensitive potassium channel opener) via an unknown mechanism. (elsevier.com)
- This study was performed to localize the mechanism of diazoxide by direct probing of sarcolemmal adenosine triphosphate-sensitive potassium channel current and by genetic deletion of channel subunits. (elsevier.com)
- Methods: Sarcolemmal adenosine triphosphate-sensitive potassium channel current was recorded in isolated wild-type ventricular mouse myocytes during exposure to Tyrode's solution, Tyrode's + 100 μmol/L diazoxide, hyperkalemic cardioplegia, cardioplegia + diazoxide, cardioplegia + 100 μmol/L pinacidil, or metabolic inhibition using whole-cell voltage clamp (N = 7-12 cells per group). (elsevier.com)
- Conclusions: Diazoxide does not open the ventricular sarcolemmal adenosine triphosphate-sensitive potassium channel but provides volume homeostasis via an SUR1-dependent pathway in mouse ventricular myocytes, supporting a mechanism of action distinct from sarcolemmal adenosine triphosphate-sensitive potassium channel activation. (elsevier.com)
- This study was performed to investigate the regulatory mechanism of cerebral blood flow of adenosine A $_{2B}$ receptor agonist in the rats, and to define whether its mechanism is mediated by adenylate cyclase, guanylate cyclase and potassium channel. (ndsl.kr)
- This effect of NECA (4 umol/I) was not blocked by pretreatment with adenylate cyclase inhibitor, MDL-12,330 (20 umol/I). But effect of NECA (4 umol/I) was blocked by pretreatment with guanylate cyclase inhibitor, LY-83,583 (10 umol/I) and pretreatment with ATP-sensitive potassium channel inhibitor, glipizide (5 umol/I). These results suggest that adenosine A $_{2B}$ receptor increases cerebral blood flow. (ndsl.kr)
- It seems that this action of adenosine A $_{2B}$ receptor is mediated via the activation of guanylate cyclase and ATP-sensitive potassium channel in the cerebral cortex of the rats. (ndsl.kr)
- This potassium channel is controlled by G proteins. (uniprot.org)
- NMDA receptors mediate leptin signaling and regulate potassium channel trafficking in pancreatic -cells. (bireme.br)
- The ability of NMDARs to regulate potassium channel surface expression and thus, -cell excitability provides mechanistic insight into the recently reported insulinotropic effects of NMDAR antagonists and therefore highlights the therapeutic potential of these drugs in managing type 2 diabetes. (bireme.br)
- This potassium channel may be involved in the regulation of insulin secretion by glucose and/or neurotransmitters acting through G-protein-coupled receptors. (abcam.com)
- Belongs to the inward rectifier-type potassium channel (TC 1.A.2.1) family. (abcam.com)
- GO annotations related to this gene include inward rectifier potassium channel activity . (genecards.org)
- Inward rectifying potassium channel that is activated by phosphatidylinositol 4,5-bisphosphate and that probably participates in controlling the resting membrane potential in electrically excitable cells. (genecards.org)
- The inward-rectifier potassium channel family (also known as 2-TM channels) include the strong inward-rectifier channels (Kir2.x), the G-protein-activated inward-rectifier channels (Kir3.x) and the ATP-sensitive channels (Kir6.x), which combine with sulphonylurea receptors. (genecards.org)
Secretion16
- Using mice lacking the sulfonylurea receptor type 1 (Sur1) subunit of KATP channels, we found that, compared with insulin secretion by WT islets, insulin secretion by Sur1-/- islets was less susceptible to oxidative stress induced by the oxidant H2O2. (nih.gov)
- Conversely, when blood glucose levels are low, the [ATP]/[ADP] ratio decreases, K ATP channels open, and insulin secretion ceases. (pnas.org)
- Despite our progress in understanding how certain mutations cause excessive insulin secretion, the molecular defects of K ATP channels caused by many PHHI mutations in the channel genes remain unknown. (pnas.org)
- The diabetes arises from suppressed insulin secretion by overactive K ATP channels in pancreatic β-cells, but the source of the motor phenotype is unknown. (sciencemag.org)
- In summary, DXM-induced alterations in stimulus-secretion coupling of wildtype islets result from a direct block of K ATP channels and are partly counteracted by inhibition of L-type Ca 2+ channels. (aspetjournals.org)
- SIGNIFICANCE STATEMENT This study shows that the use of dextromethorphan as an antidiabetic drug can cause unpredictable alterations in insulin secretion by direct interaction with K ATP and L-type Ca 2+ channels besides its actual target, the NMDA receptor. (aspetjournals.org)
- In this way, K ATP channels are able to control insulin secretion according to blood glucose levels. (elifesciences.org)
- The pivotal role of K ATP channels in insulin secretion regulation makes them an important drug target. (elifesciences.org)
- All sulfonylureas stimulate insulin secretion to reduce plasma glucose levels by inhibiting the activity of β-cell K ATP channels ( Gribble and Reimann, 2003 ). (elifesciences.org)
- Thus, these enzymes determine the open probability of K(ATP) channels and eventually the actual rate of insulin secretion. (ru.nl)
- Regulation of ATP-sensitive inwardly rectifying potassium (K ATP ) channel plays a critical role in metabolism-secretion coupling of pancreatic β-cells. (elsevier.com)
- This study examined the effects of glucagon-like peptide-1 (GLP-1) on insulin secretion alone and in combination with sulphonylureas or nateglinide, with particular attention to K-ATP channel-independent insulin secretion. (ulster.ac.uk)
- In depolarised cells, GLP-1 significantly augmented glucose-induced KATP channel-independent insulin secretion in a glucose concentration-dependent manner. (ulster.ac.uk)
- In contrast, GLP-1 exhibited a reduced but still significant insulin-releasing effect following PKA and PKC downregulation, indicating that GLP-1 can modulate K-ATP channel-independent insulin secretion by protein kinase-dependent and -independent mechanisms. (ulster.ac.uk)
- These mutations result in K-ATP channels that do not close, leading to reduced insulin secretion from beta cells and impaired blood sugar control. (medlineplus.gov)
- As in permanent neonatal diabetes mellitus, KCNJ11 gene mutations that cause transient neonatal diabetes mellitus also interfere with K-ATP channel closure and lead to a reduction in insulin secretion. (medlineplus.gov)
Kir6.235
- Bath application of H(2)O(2) reproduced PKG stimulation of Kir6.2/SUR1 but did not activate tetrameric Kir6.2LRKR368/369/370/371AAAA channels. (nih.gov)
- Enhancement of Kir6.2/SUR1 channel activity by PKG activation in transfected HEK293 cells requires the activities of the 5-hydroxydecanoate (5-HD)-sensitive factor(s) [possibly mitochondrial ATP-sensitive K + (mitoK ATP ) channels] and ROS. (nih.gov)
- Recombinant Kir6.2/SUR1 channels were expressed in HEK293 cells by transient transfection. (nih.gov)
- Loss of functional K ATP channels because of mutations in either the SUR1 or Kir6.2 channel subunit causes persistent hyperinsulinemic hypoglycemia of infancy (PHHI). (pnas.org)
- Previous studies have shown that coexpression of ΔF1388 SUR1 with Kir6.2 results in no channel activity. (pnas.org)
- Trafficking of K ATP channels requires that the endoplasmic reticulum-retention signal, RKR, present in both SUR1 and Kir6.2, be shielded during channel assembly. (pnas.org)
- To ask whether ΔF1388 SUR1 forms functional channels with Kir6.2, we inactivated the RKR signal in ΔF1388 SUR1 by mutation to AAA (ΔF1388 SUR1 AAA ). (pnas.org)
- We found that coexpression of ΔF1388 SUR1 AAA with Kir6.2 led to partial surface expression of the mutant channel. (pnas.org)
- Gain-of-function mutations in Kir6.2 ( KCNJ11 ), the pore-forming subunit of the adenosine triphosphate (ATP)-sensitive potassium (K ATP ) channel, cause neonatal diabetes. (sciencemag.org)
- The pancreatic K ATP channel is probably formed specifically of Kir6.2 and SUR1 isoforms. (rupress.org)
- The relationship between SUR1 and Kir6.2 must be determined to understand how SUR1 and Kir6.2 interact to form this unique channel. (rupress.org)
- Expression of dimeric SUR1-Kir6.2 constructs results in functional channels with very similar properties to those formed from coexpression of the parental monomers, consistent with a 1:1 SUR1/Kir6.2 stoichiometry being sufficient to form the K ATP channel. (rupress.org)
- Here in experimental hypertension, knockout of the KCNJ11 gene, encoding the Kir6.2 pore-forming subunit of the sarcolemmal ATP-sensitive potassium (KATP) channel, predisposed to heart failure and death. (ovid.com)
- Sulfonylureas are anti-diabetic medications that act by inhibiting pancreatic K ATP channels composed of SUR1 and Kir6.2. (elifesciences.org)
- Here, we present a cryo-EM structure of a hamster SUR1/rat Kir6.2 channel bound to a high-affinity sulfonylurea drug glibenclamide and ATP at 3.63 Å resolution, which reveals unprecedented details of the ATP and glibenclamide binding sites. (elifesciences.org)
- We identified Kir6.2/SUR1 and Kir6.2/SUR2 K ATP channels in rat DRG neuronal somata, peripheral nerve fibers, and glial satellite and Schwann cells, in both normal state and after painful nerve injury. (springer.com)
- We therefore used a truncated isoform of Kir6.2, that expresses ATP-sensitive channels in the absence of SUR1, to explore the mechanism of nucleotide inhibition. (ox.ac.uk)
- We present two structures of the human pancreatic KATP channel, containing the ABC transporter SUR1 and the inward-rectifier K + channel Kir6.2, in the presence of Mg 2+ and nucleotides. (elifesciences.org)
- The beta-cell K-ATP channel consists of a pore-forming subunit, Kir6.2, and a regulatory subunit, SUR1. (ox.ac.uk)
- The site at which ATP mediates channel inhibition lies on Kir6.2, while the potentiatory action of MgADP involves the nucleotide-binding domains of SUR1. (ox.ac.uk)
- Four of these are members of the inward-rectifier potassium ion channel family Kir6.x (either Kir6.1 or Kir6.2), while the other four are sulfonylurea receptors (SUR1, SUR2A, and SUR2B). (wikipedia.org)
- We examined the effects of adenine nucleotides on K(ATP) channels containing wild-type or mutant (Q52R, R201H) Kir6.2 plus either SUR1 or SUR2A. (ox.ac.uk)
- KATP channel Kir6.2 E23K variant overrepresented in human heart failure is associated with impaired exercise stress response. (cdc.gov)
- ATP-sensitive K+ (K(ATP)) channels maintain cardiac homeostasis under stress, as revealed by murine gene knockout models of the KCNJ11-encoded Kir6.2 pore. (cdc.gov)
- Blunted heart rate response during exercise is a risk factor for mortality in patients with heart failure, establishing the clinical relevance of Kir6.2 E23K as a biomarker for impaired stress performance and underscoring the essential role of K(ATP) channels in human cardiac physiology. (cdc.gov)
- A mutation in the ATP-binding site of the Kir6.2 subunit of the KATP channel alters coupling with the SUR2A subunit. (ox.ac.uk)
- When Kir6.2 containing a mutation (F333I) in the putative ATP-binding site is coexpressed with the cardiac type of regulatory K(ATP) channel subunit, SUR2A, the channel sensitivity to ATP inhibition is reduced and the intrinsic open probability (P(o)) is increased. (ox.ac.uk)
- Here we examine rundown and MgADP activation of wild-type and Kir6.2-F333I/SUR2A channels using single-channel recording, noise analysis and spectral analysis. (ox.ac.uk)
- All three approaches indicated that rundown of Kir6.2-F333I/SUR2A channels is due to a reduction in the number of active channels in the patch and that MgADP reactivation involves recruitment of inactive channels. (ox.ac.uk)
- In contrast, rundown and MgADP reactivation of wild-type and Kir6.2-G334D/SUR2A channels, and of Kir6.2-F333I/SUR1 channels, involve a gradual change in P(o). (ox.ac.uk)
- Our results suggest that F333 in Kir6.2 interacts functionally with SUR2A to modulate channel rundown and MgADP activation. (ox.ac.uk)
- It is also not a consequence of the enhanced P(o) of Kir6.2-F333I/SUR2A channels, as it is not found for other mutant channels with high P(o) (Kir6.2-I296L/SUR2A). (ox.ac.uk)
- Herein we investigated whether two polymorphisms, E23K and I337V, located in the Kir6.2 subunit of ATP-sensitive potassium channels are associated with dilated cardiomyopathy (DCM) in a Chinese population. (geneticsmr.com)
- ZD0947 is an effective activator of smooth muscle-type KATP channels (SUR2B/Kir6.1 and SUR2B/Kir6.2) but is a partial antagonist of pancreatic-type KATP channels (i.e. (sigmaaldrich.com)
- SUR1/Kir6.2) and cardiac-type KATP channels (i.e. (sigmaaldrich.com)
Glibenclamide11
- In rats, comparable doses of oral diazoxide attained appreciable concentrations in the cerebrospinal fluid, and the effects of oral diazoxide were abolished by i.c.v. administration of the KATP channel blocker glibenclamide. (jci.org)
- Indicative of the role of polyamine-dependent K ATP channels, antimycin-induced capillary cell death was markedly decreased in microvessels treated with the polyamine synthesis inhibitor, difluoromethylornithine, or the K ATP channel inhibitor, glibenclamide. (arvojournals.org)
- Davies, N.W. 1997-02-01 00:00:00 We investigated the block of KATP channels by glibenclamide in inside-out membrane patches of rat flexor digitorum brevis muscle. (deepdyve.com)
- The time course of the effect of glibenclamide suggests involvement of K(ATP) channels as effectors of endothelial IPC in vivo. (ox.ac.uk)
- We demonstrated previously that reactive microglia foster KATP-channel expression and that blocking this channel using glibenclamide administration enhances striatal neurogenesis after stroke. (edu.au)
- One of two mK ATP channel openers, pinacidil or diazoxide, was given before adenosine diphosphate in the absence or presence of an mK ATP channel antagonist, glibenclamide or 5-hydroxydecanoate. (marquette.edu)
- GLP-1 similarly augmented the K-ATP channel-independent insulin-releasing effects of tolbutamide, glibenclamide or nateglinide. (ulster.ac.uk)
- This dilator response was attenuated to 0.76 ± 0.14 mL/minute/g by inhibition of K V channels with 4-aminopyridine (0.3 mm) and to 0.11 ± 0.31 mL/minute/g by inhibition of K ATP channels with glibenclamide (3 mg/kg). (elsevier.com)
- Glibenclamide, a KATP-channel blocker inhibited the cromakalim-induced concentration-related relaxation of spontaneous contractions with a significant increase in its mean IC50. (bvsalud.org)
- The present results suggest that in the goat detrusor muscle, agonist and EFS-induced contractile responses were more potently inhibited by cromakalim than pinacidil with activation of glibenclamide sensitive KATP channels. (bvsalud.org)
- Characterization, purification and affinity labeling of the brain [3H]glibenclamide binding protein, a putative neuronal ATP-regulated K+ channel. (springer.com)
Diazoxide12
- Oral administration of the KATP channel activator diazoxide under fixed hormonal conditions substantially decreased EGP in nondiabetic humans and Sprague Dawley rats. (jci.org)
- Compared with wild-type channels, the mutant channels have reduced ATP sensitivity and do not respond to stimulation by MgADP or diazoxide. (pnas.org)
- The OGD and pMCAO effects were reduced by activating K ATP channel by diazoxide. (empr.com)
- These effects of diazoxide were blocked by the mitoK ATP channel blocker 5-hydroxydecanoate (500 μmol/L). These results indicate that opening of mitoK ATP channels prevents a mitochondrial Ca 2+ overload in association with ΔΨ m depolarization and thereby protects myocardium against ischemic damage. (ahajournals.org)
- The rats received low-dose (0.15 mg/kg) or high-dose (0.5 mg/kg) fasudil or diazoxide, an m-KATP channel opener, at 10 mg/kg, just before reperfusion under normoglycemic or hyperglycemic conditions. (springermedizin.de)
- Autofluorescence of flavoproteins of the respiratory chain in the isolated rabbit cardiomyocytes was registered before and after application of mitochondrial KATP channel opener diazoxide (100 and 400 microM). (inserm.fr)
- These studies indicate for die first time that the mitochondrial K-ATP channel opener diazoxide improves neurological function after spinal cord ischemia and reperfusion by diminishing levels of reactive oxygen species, decreasing DNA oxidative damage, and inhibiting caspase-dependent and -independent apoptotic pathways while preserving mitochondrial structure. (elsevier.com)
- Diazoxide was found to depolarize mitochondria from wildtype cardiomyocytes but not Ex5 mitochondria, consistent with disrupted mitochondrial KATP channels. (ahajournals.org)
- Functionally, glucose-stimulated cytosolic Ca 2+ ([Ca 2+ ] i ) increase was blunted by insulin or diazoxide, a K ATP channel opener. (elsevier.com)
- To investigate the therapeutic potential of drugs that activate KATP channels in AD, we first characterized the effects of the KATP channel opener diazoxide on cultured neurons, and then determined its ability to modify the disease process in the 3xTgAD mouse model of AD. (elsevier.com)
- Diazoxide hyperpolarized neurons, reduced the frequency of action potentials, attenuated Ca 2+ influx through NMDA receptor channels, and reduced oxidative stress. (elsevier.com)
- Our findings show that diazoxide can ameliorate molecular, cytopathological, and behavioral alterations in a mouse model of AD suggesting a therapeutic potential for drugs that activate KATP channels in the treatment of AD. (elsevier.com)
Sulfonylurea receptor2
- The Abcc9 gene encodes the major regulatory subunit in the heart, sulfonylurea receptor 2 (SUR2), as well as smaller mitochondria-enriched proteins that contribute to sulfonylurea-insensitive KATP channels. (ahajournals.org)
- High glucose increased plasmalemmal sulfonylurea receptor 1 (SUR1), a component of K ATP channel as well as exogenous insulin treatment. (elsevier.com)
Kir6.13
- In mice, the Coxsackievirus B3 replicates to higher titers in the hearts of mayday mutant animals, which are deficient in the Kir6.1 subunit of K(ATP) channels, than in controls. (scripps.edu)
- The results showed that miR-20 was remarkably down-regulated, while the KATP subunit Kir6.1 was significantly up-regulated, during myocardial ischemia. (deepdyve.com)
- It was concluded that miR-20 may regulate myocardiac ischemia by targeting KATP subunit Kir6.1 to accelerate the cell apoptosis. (deepdyve.com)
Intracellular13
- The ATP-sensitive potassium (K(ATP)) channel couples intracellular metabolic state to membrane excitability. (nih.gov)
- In this study, we further investigated the intracellular mechanism underlying PKG stimulation of neuronal K(ATP) channels. (nih.gov)
- During glucose stimulation, the intracellular ATP to ADP ratio increases following glucose metabolism, which favors channel closure by ATP, resulting in membrane depolarization, Ca 2+ influx, and exocytosis of insulin granules. (elifesciences.org)
- Particularly important is the class of K+ (KATP) channels modulated by intracellular ATP, which are normally closed at physiological intracellular ATP concentrations (ATPi) but open when ATPi decreases. (eurekaselect.com)
- ATP-sensitive K+ (KATP) channels are both inhibited and activated by intracellular nucleotides, such as ATP and ADP. (ox.ac.uk)
- In many excitable cells, KATP channels respond to intracellular adenosine nucleotides: ATP inhibits while ADP activates. (elifesciences.org)
- When exposed to milimolar concentrations of intracellular ATP, these channels become quiescent. (elifesciences.org)
- 2. At a holding potential of +40 mV, spermine at the intracellular membrane surface reduced the KATP channel open probability (Popen) in a dose-dependent manner. (meta.org)
- In response to intracellular energy supply, ATP-sensitive potassium (KATP) channels alter membrane potential and mediate cell stress response. (ahajournals.org)
- Loss of KATP channel activity during fatigue results in excessive intracellular Ca2+ ([Ca2+]i) levels, likely entering the fiber through L-type Ca2+ channels. (uottawa.ca)
- For example, the ATP-sensitive K + channel regulates electrical excitability in multiple tissues in response to the intracellular ATP concentration 39 . (nature.com)
- Since the Cl flow into or out of the cell plays a crucial role in hyperpolarizing or depolarizing the cells, respectively, the impact of intracellular Ca concentration on these channels is attracting a lot of attentions. (bireme.br)
- Intracellular ADP activates K+ channels that are inhibited by ATP in an insulin-secreting cell line. (springer.com)
Regulation14
- While there is evidence for central regulation of EGP by activation of hypothalamic ATP-sensitive potassium (KATP) channels in rodents, whether these central pathways contribute to regulation of EGP in humans remains to be determined. (jci.org)
- This study tests the hypothesis that glycolytic regulation of KATP channel activity is altered in myocardial hypertrophy. (biomedsearch.com)
- This signaling pathway may contribute to neuroprotection against ischemic injury and regulation of neuronal excitability and neurotransmitter release by modulating the function of neuronal K(ATP) channels. (nih.gov)
- 2 , 3 Although this functional specialization within the retinal microvasculature appears to be important for the effective regulation of local perfusion, we hypothesized that the abundance of K ATP channels may boost the vulnerability of the capillaries to hypoxic damage. (arvojournals.org)
- We aimed at investigating regulation of SUR2, the regulatory subunit of KATP, via a systems biology approach. (ahajournals.org)
- Potassium selective ion channels play an important role in the regulation of vascular tone. (eurekaselect.com)
- Physiologic regulation of these channels is not fully understood. (eurekaselect.com)
- Eva Pongo, Ines Nevelsteen, Erin Liem, Willem Flameng and Kanigula Mubagwa, " Interaction Between KATP-Channels and Protein Kinase C in the Regulation of Basal Coronary Flow", Vascular Disease Prevention (Discontinued) (2004) 1: 141. (eurekaselect.com)
- An adenylate kinase is involved in KATP channel regulation of mouse pancreatic beta cells. (ru.nl)
- To explore phosphotransfer signalling pathways in more detail, we examined whether K(ATP) channel regulation in beta cells is determined by a metabolic interaction between adenylate kinase (AK) and CK. (ru.nl)
- This suggests that AK-catalysed ADP production in the vicinity of the channels is involved in K(ATP) channel regulation. (ru.nl)
- Metabolic regulation is mediated by changes in ATP and MgADP concentration, which inhibit and potentiate channel activity, respectively. (ox.ac.uk)
- Regulation of ATP-sensitive K' channels in insulinoma cells: Activation by somatostatin and kinase C and the role of cAMP. (springer.com)
- Pharmacology and regulation of ATP-sensitive K+ channels. (springer.com)
Receptors7
- K ATP channels are octameric complexes composed of four sulfonylurea receptors (SUR.x) and four inward rectifier potassium channels Kir6.x ( 4 - 7 ). (pnas.org)
- The stimulatory effect of DXO seems to be based on a combined antagonism on K ATP channels and NMDA receptors and already occurs under resting conditions. (aspetjournals.org)
- This study was designed to elucidate the contribution of adenosine A 2A and A 2B receptors to coronary reactive hyperemia and downstream K + channels involved. (elsevier.com)
- These data indicate that A 2A receptors contribute to coronary vasodilation in response to cardiac ischemia via activation of K V and K ATP channels. (elsevier.com)
- 16-18 ] Enhanced recovery of postischemic reperfused myocardium produced by isoflurane was partially mediated by activation of type 1 adenosine (A 1 ) receptors coupled to K ATP channels. (asahq.org)
- NMDA receptors (NMDARs) are Ca -permeant, ligand-gated ion channels activated by the excitatory neurotransmitter glutamate and have well-characterized roles in the nervous system. (bireme.br)
- Antidiabetic sulfonylureas control action potential in heart cells via high affinity receptors that are linked to ATP-dependent K+ channels. (springer.com)
Loss of KATP channel activity1
- Sur1-/- mice were less susceptible than WT mice to streptozotocin-induced beta cell destruction and subsequent hyperglycemia and death, which suggests that loss of KATP channel activity may protect against streptozotocin-induced diabetes in vivo. (nih.gov)
Plasma membrane KATP channels1
- The presence of nucKATP was confirmed by the discovery that isolated patches of nuclear membrane possess properties, both kinetic and pharmacological, similar to plasma membrane KATP channels. (wikipedia.org)
Mutations11
- Genetic studies have identified ≈50 PHHI mutations in the K ATP channel genes ( 11 , 12 ). (pnas.org)
- Some mutations in the C-terminus also markedly increased the channel open probability, which may account for the decrease in apparent ATP sensitivity. (ox.ac.uk)
- As in aldosterone-producing adenomas (described above), KCNJ5 gene mutations result in production of less-selective potassium channels. (medlineplus.gov)
- K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. (medlineplus.gov)
- A Meta-Analysis of Somatic KCNJ5 K(+) Channel Mutations In 1636 Patients With an Aldosterone-Producing Adenoma. (medlineplus.gov)
- To evaluate the dose of exendin-(9-39) required to elevate fasting blood glucose levels in subjects with congenital hyperinsulinism due to KATP channel mutations. (clinicaltrials.gov)
- Functional effects of naturally occurring KCNJ11 mutations causing neonatal diabetes on cloned cardiac KATP channels. (ox.ac.uk)
- Both mutations also increased resting whole-cell K(ATP) currents through heterozygous SUR1-containing channels to a greater extent than for heterozygous SUR2A-containing channels. (ox.ac.uk)
- Understanding the molecular mechanism of action of these mutations has provided valuable insight into the relationship between the structure and function of the K(ATP) channel. (ox.ac.uk)
- Most of these mutations change single protein building blocks (amino acids) in the protein sequence, reducing or preventing activity of the K-ATP channels. (medlineplus.gov)
- Other KCNJ11 gene mutations that have a relatively mild effect on K-ATP channel function as compared to that seen in permanent neonatal diabetes mellitus (see above) cause a condition called transient neonatal diabetes mellitus. (medlineplus.gov)
Activation20
- These results suggest that activation of hypothalamic KATP channels may be an important regulator of EGP in humans and that this pathway could be a target for treatment of hyperglycemia in type 2 diabetes mellitus. (jci.org)
- The defect in K ATP channel trafficking in PHPT-1 -/- β cells was due to the failure of PHPT-1 to directly activate transient receptor potential channel 4 (TRPC4) resulting in decreased Ca 2+ influx and impaired downstream activation of AMPK. (diabetesjournals.org)
- Recently, we demonstrated that neuronal K(ATP) channels are functionally enhanced by activation of a nitric oxide (NO)/cGMP/cGMP-dependent protein kinase (PKG) signaling cascade. (nih.gov)
- These reagents also ablated NO-induced K(ATP) channel stimulation and prevented the shifts in the single-channel open- and closed-time distributions resulting from PKG activation and NO induction. (nih.gov)
- Altogether, in this report we provide novel evidence that activation of PKG stimulates neuronal K(ATP) channels by modulating intrinsic channel gating via a 5-HD-sensitive factor(s)/ROS/Ca(2+)/calmodulin signaling pathway that requires the presence of the SUR1 subunit. (nih.gov)
- Thus, in pancreatic β cells, the [ATP]/[ADP] ratio increases in response to increases in blood glucose levels, leading to K ATP channel closure, membrane depolarization, activation of voltage-gated Ca 2+ channels, and insulin release. (pnas.org)
- HealthDay News - Treatment with sulfonylureas (ATP-sensitive potassium [K ATP ] channel blockers) may inhibit the neuroprotective effects of K ATP channel activation and increase the risk of stroke, according to an experimental study published online May 13 in Diabetes . (empr.com)
- We also found that activation of the polyamine/K ATP channel/Ca 2+ influx/CICR pathway not only boosted the vulnerability of retinal capillaries to hypoxia, but also caused the contraction of capillary pericytes, whose vasoconstrictive effect may exacerbate hypoxia. (arvojournals.org)
- Fasudil induces PostC against myocardial infarction via activation of m-KATP channels in the rat. (springermedizin.de)
- KATP channel activation induces ischemic preconditioning of the endothelium in humans in vivo. (ox.ac.uk)
- Mechanistic studies employing hyperpolarising concentrations of potassium or glybenclamide revealed that these relaxant effects are mediated via specific activation of ATP-sensitive potassium channels. (nih.gov)
- 3: Activation of the ATP-sensitive potassium channels: A novel pharmacological approach to myocardial protection? (ebook.de)
- In this study, we investigated whether the microglial KATP-channel directly influences the activation of neural precursor cells (NPCs) from the subventricular zone using transgenic Csf1r-GFP mice. (edu.au)
- Mg-nucleotide activation of SUR1, but not SUR2A, channels was markedly increased by the R201H mutation. (ox.ac.uk)
- These effects are partially blocked by glyburide pretreatment, indicating that KATP channel activation by isoflurance may mediate these cardioprotective effects. (mcw.edu)
- This alleviates energy demand within the fiber, as activation of the channel reduces ATP consumption from cellular ATPases. (uottawa.ca)
- The rapid upstroke of the AP of ventricular and atrial myocytes and Purkinje fibers is due to the activation of voltage gated Na+ channels allowing Na to flow into the cell (negative current), similarly to skeletal and nervous tissue. (brainscape.com)
- K ATP channel activation has been shown to play an important role to mediate the acute memory phase of ischemic preconditioning. (asahq.org)
- 16-18 ] The present investigation tested the hypothesis that isoflurane directly preconditions myocardium against myocardial infarction via activation of K ATP channels and that this effect is associated with an acute memory phase, thus mimicking ischemic preconditioning. (asahq.org)
- Conversely, activation of NMDARs mimicked the effect of leptin, causing Ca influx, AMPK activation, and increased trafficking of K and Kv2.1 channels to the plasma membrane, and triggered membrane hyperpolarization. (bireme.br)
Ischemia9
- To investigate the role of K-ATP channels in stabilization of ionic homeostasis at earlier stages of ischemia. (arvojournals.org)
- An oxygen-glucose deprivation protocol (OGD) was used to mimic ischemia, and glybenclamide (0.1 mM) was applied to block K-ATP channels. (arvojournals.org)
- 2) K-ATP channels play a role in natural protection from ischemia, delaying the collapse of ionic homeostasis. (arvojournals.org)
- 3) A promising strategy against ischemia might be the mobilization of K-ATP channel based defense, possibly using preconditioning. (arvojournals.org)
- Coronary KATP channels are activated by adenosine released during exercise, hypoxia or ischemia. (eurekaselect.com)
- A mechanism has been proposed for the cell's KATP reaction to hypoxia and ischemia. (wikipedia.org)
- In cases of diabetes, KATP channels cannot function properly, and a marked sensitivity to mild cardiac ischemia and hypoxia results from the cells' inability to adapt to adverse oxidative conditions. (wikipedia.org)
- It is not known if anesthetic preconditioning (APC) applies as well to hypothermic ischemia and reperfusion and if K(ATP) channels are involved. (asahq.org)
- Anesthetic preconditioning occurs after long-term hypothermic ischemia, and the infarct size reduction is the result, in part, of mitochondrial K(ATP) channel opening. (asahq.org)
Activate KATP channels1
- Lactate failed to activate KATP channels in both cell types. (biomedsearch.com)
Mutation3
- The RKR → AAA mutation alone has no effect on channel properties. (pnas.org)
- Echocardiography, cardiac perfusion stress imaging, invasive electrophysiology with isoproterenol provocation, genomic DNA sequencing of KATP channel genes, exclusion of mutation in 2,000 individuals free of AF, reconstitution of channel defect with molecular phenotyping, and verification of pathogenic link in targeted knockout. (ovid.com)
- KATP channelopathy caused by missense mutation (Thr1547Ile) of the ABCC9 gene conferring predisposition to adrenergic AF originating from the vein of Marshall. (ovid.com)
Adenosine Triphosphate4
- In this study, it was hypothesized that their specialized physiology, which includes being the predominant microvascular location of functional adenosine triphosphate-sensitive potassium (K ATP ) channels, boosts their susceptibility to hypoxia-induced cell death. (arvojournals.org)
- 1 - 3 For example, most of the functional adenosine triphosphate-sensitive potassium (K ATP ) channels are located in the capillaries. (arvojournals.org)
- As the hyperactivity (i.e. more channels remain in the open state) of the vascular adenosine triphosphate (ATP)- sensitive type of potassium (KATP) channels results in vasodilatation, this channel has been implicated in the pathogenesis of septic shock. (ucl.ac.uk)
- This investigation examined the role of myocardial adenosine triphosphate-regulated potassium (KATP) channels in isoflurane-induced enhancement of myocardial function after reversible tissue injury produced by a 15-min left anterior descending coronary artery occlusion (LAD) and reperfusion. (mcw.edu)
Pancreatic beta-cell1
- CONCLUSIONS/INTERPRETATION: We propose that phosphotransfer events mediated by AK and CK play an important role in determining the effective concentrations of ATP and ADP in the microenvironment of pancreatic beta cell K(ATP) channels. (ru.nl)
Inward rectifier1
- Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. (uniprot.org)
Membrane potential5
- We tested whether opening of mitochondrial ATP-sensitive K + (mitoK ATP ) channels depolarizes mitochondrial membrane potential (ΔΨ m ) and thereby prevents the mitochondrial Ca 2+ overload. (ahajournals.org)
- In the presence of higher glucose metabolism, and consequently increased relative levels of ATP, the KATP channels close, causing the membrane potential of the cell to depolarize, activating voltage-gated calcium channels, and thus promoting the calcium-dependent release of insulin. (wikipedia.org)
- ATP-sensitive K + channels constitute a new class of K + channels that link membrane potential variations to the bioenergetic situation of the cell (Noma, 1983). (springer.com)
- What causes K-ATP channels to open and what does the opening do to the membrane potential? (brainscape.com)
- These K + channels hyperpolarize the membrane potential and inhibit neuronal excitability. (jneurosci.org)
Metabolic10
- In both cell types, KATP channels were activated in the absence of PEP, inhibited when PEP was added and activated again when PEP was removed, indicating the cells retained metabolic integrity and generated ATP in the proximity of their KATP channels. (biomedsearch.com)
- Mammalian SUR genes are associated with K ATP (ATP-sensitive potassium) channels, which are involved in metabolic homeostasis. (pnas.org)
- ATP-sensitive potassium channels (K ATP ) couple metabolic signals to cell excitability. (pnas.org)
- These gating properties are crucial for the ability of the channel to sense metabolic changes in cells. (pnas.org)
- Defective decoding of hypertension-induced metabolic distress signals in the KATP channel knockout set in motion pathological calcium overload and aggravated cardiac remodeling through a calcium/calcineurin-dependent cyclosporine-sensitive pathway. (ovid.com)
- Rescue of the failing KATP knockout phenotype was achieved by alternative control of myocardial calcium influx, bypassing uncoupled metabolic-electrical integration. (ovid.com)
- Changes in the transcription of these genes, and thus the production of KATP channels, are directly linked to changes in the metabolic environment. (wikipedia.org)
- The degree to which particular compounds are able to regulate KATP channel opening varies with tissue type, and more specifically, with a tissue's primary metabolic substrate. (wikipedia.org)
- In pancreatic beta cells, ATP is the primary metabolic source, and the ATP/ADP ratio determines KATP channel activity. (wikipedia.org)
- Under metabolic stress, the channels open, reducing membrane excitability, Ca2+ release and force production. (uottawa.ca)
SUR2B1
- 1 and SUR2B of KATP channels in the colon devoid of mucosa and submucosa (n = 10, P (cxcrinhibitor.com)
Pharmacological3
- Pharmacological studies suggest mitochondrial KATP channels are critical regulators of cell stress, however the molecular composition of this channel has been unclear. (ahajournals.org)
- Molecular, biophysical, and pharmacological properties of calcium-activated chloride channels. (bireme.br)
- An outline of the present knowledge on the impact of mKATP opening on ROS production, and ROS signaling events triggered by mKATP opening is provided, in order to find a link between bioenergetic effects of mKATP channels functioning and multiple pathways of cytoprotection afforded by pharmacological mKATP channels openers. (novapublishers.com)
Pathway1
- The vulnerability of retinal capillaries to hypoxia is boosted by a mechanism involving the polyamine/K ATP channel/Ca 2+ influx/CICR pathway. (arvojournals.org)
Blocker5
- Surprisingly, this attenuated pressor response to PNU-37883A could be partially reversed by the autonomic ganglion blocker, pentolinium, suggesting that during sepsis the vascular KATP channel may be inhibited in vivo by the high sympathetic tone. (ucl.ac.uk)
- In another group, rats received 5-hydroxydecanoic acid (5HD), an m-KATP channel blocker, at 10 mg/kg, before high-dose fasudil. (springermedizin.de)
- The changes were much more dramatic when the K-ATP channel blocker glybenclamide was applied during OGD. (arvojournals.org)
- HCN channel blocker: blocker of neuronal I h , related cardiac I f channels and ATP-sensitive K ir channels. (sigmaaldrich.com)
- We recorded robust K + currents in the voltage range of the M-current, which were inhibited by the selective KCNQ channel blocker 10,10-bis(4-pyridinylmethyl)-9(10 H )-anthracenone dihydrochloride (XE991) (40 μ m ), in both intact males and ovariectomized, 17β-estradiol (E2)-treated females. (jneurosci.org)
Diabetes1
Openers7
- 7: Is there a potential role for the KATP openers in the treatment of Angina? (ebook.de)
- KATP Channel Openers Have Opposite Effects on Mitochondrial Respiratio" by Matthias L. Riess, Amadou K.S. Camara et al. (marquette.edu)
- We investigated the effects of two different K ATP channel openers and antagonists on mitochondrial respiration under two different energetic conditions. (marquette.edu)
- When ATP synthase was inhibited by oligomycin to decrease [ATP], both mK ATP channel openers accelerated respiration for both substrate groups. (marquette.edu)
- Therefore, the effects of mK ATP channel openers on mitochondrial function likely depend on the experimental conditions and the cell's underlying energetic state. (marquette.edu)
- Effect of KATP channel openers on myogenic and neurogenic responses in goat urinary bladder. (bvsalud.org)
- Structure-activity relationship of K+ channel openers. (springer.com)
Kinetics2
- Trypsin (20 micrograms/ml) irreversibly enhanced channel activity around twofold by reducing the interburst intervals without altering the burst kinetics. (ox.ac.uk)
- 4. Analysis of KATP single channel kinetics showed that spermine inhibited the channel by decreasing the mean open time and introducing transitions to a long closed state. (meta.org)
Molecular2
- Our results establish defective trafficking of K ATP channels as a molecular basis of PHHI and show that F1388 in SUR1 is critical for normal trafficking and function of K ATP channels. (pnas.org)
- The intact KCNJ11-encoded KATP channel is thus a required safety element preventing hypertension-induced heart failure, with channel dysfunction a molecular substrate for stress-associated channelopathy in cardiovascular disease. (ovid.com)
Oxidative stress3
- Suppression of KATP channel activity protects murine pancreatic beta cells against oxidative stress. (nih.gov)
- Here, we examined the effects of genetic and pharmacologic ablation of KATP channels on loss of mouse beta cell function and viability following oxidative stress. (nih.gov)
- One significant implication of the link between cellular oxidative stress and increased KATP production is that overall potassium transport function is directly proportional to the membrane concentration of these channels. (wikipedia.org)
Antagonist2
- Neither mK ATP channel antagonist abolished these effects. (marquette.edu)
- Glyburide, a KATP channel antagonist, attenuates the cardioprotective effects of isoflurane in stunned myocardium. (mcw.edu)
Decreases1
- Hypertrophy decreases cardiac KATP channel responsiveness to exogenous and locally generated (glycolytic) ATP. (biomedsearch.com)
Humans1
Glucose5
- PHPT-1 -/- mice exhibited neonatal hyperinsulinemic hypoglycemia due to impaired trafficking of K ATP channels to the plasma membrane in pancreatic β cells in response to low glucose and leptin and resembled patients with congenital hyperinsulinism (CHI). (diabetesjournals.org)
- Neuronal injury induced by oxygen-glucose deprivation (OGD) in vitro and permanent middle cerebral artery occlusion (pMCAO) in vivo was increased by blocking K ATP channel by tolbutamide. (empr.com)
- The K-ATP channels are embedded in cell membranes, where they open and close in response to the amount of glucose in the bloodstream. (medlineplus.gov)
- Closure of the K-ATP channels in response to increased glucose triggers the release of insulin out of beta cells and into the bloodstream, which helps control blood sugar levels. (medlineplus.gov)
- Glucose induces closure of single potassium channels in isolated rat pancreatic ß cells. (springer.com)
Cardiac myocytes4
- In 1983, Akinori Noma made the first recordings of ATP-dependent potassium channels in rat cardiac myocytes ( Noma, 1983 ). (elifesciences.org)
- In membrane patches excised from cardiac myocytes, ATP-dependent K + -channels spontaneously open in electrolyte solutions devoid of nucleotides. (elifesciences.org)
- 6. Our results indicate that natural polyamines influence native KATP channel gating in cardiac myocytes. (meta.org)
- KATP channels were first identified in cardiac myocytes by the Akinori Noma group in Japan. (wikipedia.org)
Mitochondrial ATP-sensitive2
- Mitochondrial ATP-sensitive K + (mitoK ATP ) channels are thought to play a key role in cardioprotection, 1 but the crucial question remains as to why the opening of mitoK ATP channels can be so protective. (ahajournals.org)
- The current study was carried out to determine whether fasudil hydrochloride (fasudil), a Rho-kinase inhibitor, has myocardial postconditioning (PostC) activity under hyperglycemia as well as normoglycemia, and if so, whether the effects could be mediated by mitochondrial ATP-sensitive potassium (m-KATP) channels. (springermedizin.de)
Physiology1
- However, the translational significance of K(ATP) channels in human cardiac physiology remains largely unknown. (cdc.gov)
Blockade2
- This was abolished by mK ATP channel blockade. (marquette.edu)
- In contrast, under energetically less physiological conditions, mK ATP channel opening can be evidenced by accelerated respiration and blockade by antagonists. (marquette.edu)
Mouse pancreatic beta cells1
- The inside-out configuration of the patch-clamp method was used to study the effects of trypsin on the activity of ATP-sensitive potassium (K-ATP) channels from isolated mouse pancreatic beta-cells. (ox.ac.uk)
Functional4
- We demonstrate here that the lack of functional expression is due to failure of the mutant channel to traffic to the cell surface. (pnas.org)
- Because K ATP channels may have diverse functional roles in neurons and glia, further studies are needed to explore the potential of K ATP channels as targets of therapies against neuropathic pain and neurodegeneration. (springer.com)
- We also characterized new functional variants of human ABCC8, ABCC9, KCNJ8, and KCNJ11 genes encoding for the K ATP channel and analyzed their association with ALS risk, rate of progression, and survival in a Spanish ALS cohort. (cdc.gov)
- It has been demonstrated that when mouse muscle lacking functional KATP channels are stimulated to fatigue, ATP levels become significantly lower than wild type levels. (uottawa.ca)
Genes2
- Four genes have been identified as members of the KATP gene family. (wikipedia.org)
- We then sequenced the exons and regulatory regions of K ATP channel genes from a subset of 28 ALS patients and identified 50 new genetic variants. (cdc.gov)
Induces1
Gene2
- Potassium channels produced from the KCNJ5 gene are found in several tissues, including the adrenal glands, which are small hormone-producing glands located on top of each kidney. (medlineplus.gov)
- KCNJ12 (Potassium Voltage-Gated Channel Subfamily J Member 12) is a Protein Coding gene. (genecards.org)
Receptor1
Mice1
- In islets of K ATP channel-deficient SUR1 knockout mice the elevating effects of 100 µM DXM on [Ca 2+ ] c and insulin release were completely lost. (aspetjournals.org)
Regulate2
- ATP-sensitive potassium (K ATP ) channels in neurons mediate neuroprotection, they regulate membrane excitability, and they control neurotransmitter release. (springer.com)
- In addition to ATP, other co-factors also regulate KATP. (elifesciences.org)
Inhibits1
- ATP inhibits channel activity whereas ADP, in the presence of Mg 2+ , antagonizes the inhibitory effect of ATP and stimulates channel activity ( 8 ). (pnas.org)
Sensitivity2
- RESULTS: The ATP sensitivity of K(ATP) channels was higher in i/o patches than in permeabilised beta cells (oca). (ru.nl)
- By virtue of their sensitivity to both ATP and ADP, these channels are thought to couple cellular metabolism to membrane excitability. (elifesciences.org)
Inhibitory effect3
- No effect on the single channel conductance or the inward rectification produced by internal Mg2+ was observed: however, the protease did reduce the inhibitory effect of Mg2+ on channel activity. (ox.ac.uk)
- The protease also reduced the inhibitory effect of ATP on channel activity, increasing the dissociation constant from 7 to 49 microM. (ox.ac.uk)
- Trypsin removed the activating effect of ADP (0.1 mmol/l) on channel activity and reduced the inhibitory effect of tolbutamide (0.5 mmol/l). (ox.ac.uk)