- currents
- In an effort to understand the functional consequences of particular channel mutations, cDNA techniques have been utilised to express mutant and normal channels in in vitro biological systems, allowing currents to be measured across either groups of channels in membrane patches or single channels. (bmj.com)
- The voltage-gated K+ channels that provide the outward currents of action potentials have similarities to bacterial K+ channels. (wikipedia.org)
- Familial hemiplegic migraine is caused by mutations in the calcium channel, Ca V 2.1, which conducts P/Q-type calcium currents that initiate neurotransmitter release. (jneurosci.org)
- The inherited LQTS associated KCNQ1/KCNE1 and HERG/KCNE2 channel mutations cause a decrease in net repolarizing current I K by reducing potassium currents through "dominant-negative" or "loss-of-function" mechanisms, whereas the aLQTS is the result of I K -blockade. (aspetjournals.org)
- Intracellular application of 20 μ m PIP 2 slowed the rundown of KCNQ2/3 currents expressed in COS-1 or tsA-201 cells, and 100 μ m PIP 2 produced a small potentiation of native M-current bullfrog sympathetic neurons. (jneurosci.org)
- We show that changes in firing patterns are caused by neurotrophin-dependent regulation of at least four voltage-gated currents: the sodium current and the M-type, delayed rectifier, and calcium-dependent potassium currents. (jneurosci.org)
- Here we demonstrate that activation of the neurotrophin receptors, p75 or TrkA, leads to expression of distinct firing patterns through differential regulation of sodium and potassium currents. (jneurosci.org)
- Removal of the NH2-terminal domain, either by trypsin or molecular biology techniques, results in a b-subunit that does not inactivate the channel, so the currents are sustained and more suitable for kinetic and Ca2+ sensitivity comparisons. (epfl.ch)
- Calmodulin also was able to modulate the inactivation kinetics of Nav1.6, but not Nav1.4, currents in a calcium-dependent manner. (epfl.ch)
- subunits
- Ion channels are made up of subunits, which combine to form structures with a central aqueous pore. (bmj.com)
- Based on sequence homology of the hydrophobic transmembrane cores, the alpha subunits of voltage-gated potassium channels are grouped into 12 classes. (wikipedia.org)
- These subunits do not conduct current on their own but rather modulate the activity of Kv channels. (wikipedia.org)
- Typically, vertebrate voltage-gated K+ channels are tetramers of four identical subunits arranged as a ring, each contributing to the wall of the trans-membrane K+ pore. (wikipedia.org)
- Channel mutation studies have revealed the parts of the subunits that are essential for ion selectivity. (wikipedia.org)
- As K+ passes through the pore, interactions between potassium ions and water molecules are prevented and the K+ interacts with specific atomic components of the Thr-Val-Gly-[YF]-Gly sequences from the four channel subunits . (wikipedia.org)
- Voltage-gated Na + channels in the brain are complexes of a 260 kDa α subunit in association with auxiliary β subunits (β1-β4) of 33-36 kDa (Catterall, 2000). (jneurosci.org)
- 50% in the transmembrane domains of human sodium channel α subunits and those of the simplest multicellular eukaryotes. (jneurosci.org)
- The mammalian genome contains nine functional voltage-gated sodium channel α subunits, which differ in patterns of tissue expression and biophysical properties. (jneurosci.org)
- This protein belongs to the potassium channel KCNE family and is one five single transmembrane domain voltage-gated potassium (Kv) channel ancillary subunits. (wikipedia.org)
- The number of functionally distinct channels in native tissues is further increased by heteromultimeric assembly of potassium channel α-subunits with other α- and β-subunits and other modifications such as alternative splicing of mRNAs, glycosylation, and phosphorylation. (aspetjournals.org)
- In contrast to the b1 subunit, the b2 subunit confers low CTX affinity compared with channels formed only by alpha-subunits (Xia ). (epfl.ch)
- Thus, the selectivity of the cognitive enhancer is dependent on the type of subunits colocalized with particular K + channels. (aspetjournals.org)
- action potentials
- Pharmacological investigations suggested that axonal action potential repolarization in both cell types depends critically upon Kv1 channels, whereas the axonal and somatic action potentials of somatostatin-expressing interneurons also depend on BK Ca 2+ -activated K + channels. (jneurosci.org)
- ligand gated
- The two principal classes are voltage and ligand gated channels. (bmj.com)
- A ligand gated ion channel opens following binding of a ligand to the receptor portion of the channel. (bmj.com)
- neuronal
- We studied here the coupling of different molecularly defined P2Y receptors to neuronal G protein-gated inward rectifier K + (GIRK) channels. (aspetjournals.org)
- Moreover, each type of neuronal BK channels are differentially sensitive to PKA-dependent phosphorylation. (epfl.ch)
- Leptin activates BK channels via PI 3-kinase controlling neuronal excitability. (epfl.ch)
- Both muscle and neuronal Na+ channels are as sensitive to ranolazine block as their cardiac counterparts. (epfl.ch)
- proteins
- Interestingly, the HVCN1 and Putative tyrosine-protein phosphatase proteins do not contain an expected ion conduction pore domain, but rather have homology only to the voltage sensor domain of voltage gated ion channels. (wikipedia.org)
- Study of the altered properties of voltage-gated K+ channel proteins produced by mutated genes has helped reveal the functional roles of K+ channel protein domains and even individual amino acids within their structures. (wikipedia.org)
- We show that rat vestibular calyces express an unusual mix of voltage-gated Na and K channels and scaffolding, cell adhesion, and extracellular matrix proteins, which may hold the ion channels in place. (pubmedcentralcanada.ca)
- Cation channels are membrane proteins that provide controlled pathways for ion passage through cellular membranes. (aspetjournals.org)
- The importance of cation channels is also amplified by the fact that many therapeutic drugs mediate their effects by targeting these proteins. (aspetjournals.org)
- There is evidence of changes in BK channel activity by phosphorylation and/or interaction by G proteins, by mechanical stretch, and by various endothelium-derived vasoactive substances . (epfl.ch)
- Calmodulin, a 16.7 kDa protein that is expressed in virtually all eukaryotic cells, can induce changes in target proteins via its binding per se and in response to changes in calcium concentration . (epfl.ch)
- mutations
- Genetic approaches include screening for behavioral changes in animals with mutations in K+ channel genes. (wikipedia.org)
- Studies of genetic forms of epilepsy, chronic pain, and migraine caused by mutations in ion channels have given crucial insights into molecular mechanisms, pathogenesis, and therapeutic approaches to complex neurological disorders. (jneurosci.org)
- Gain-of-function missense mutations in the brain type-I sodium channel Na V 1.1 are a primary cause of generalized epilepsy with febrile seizures plus. (jneurosci.org)
- Loss-of-function mutations in Na V 1.1 channels cause severe myoclonic epilepsy of infancy, an intractable childhood epilepsy. (jneurosci.org)
- Mutations in the peripheral sodium channel Na V 1.7 cause familial pain syndromes. (jneurosci.org)
- Because of the importance of their functions and the complexity of their structures, these two ion channels are targets for numerous mutations that cause diseases of hyperexcitability, including epilepsy, migraine, chronic pain, periodic paralysis, and cardiac arrhythmia. (jneurosci.org)
- Channels might lose or gain function as a result of mutations in the promotor or codings region of a gene. (aspetjournals.org)
- However, myotonia caused by CLCN1 mutations can occasionally be clinically indistinguishable from myotonia caused by sodium channel mutations ( SCN4A mutations) resulting in the similar disease paramyotonia congenita . (wikipedia.org)
- accessory subunit
- MiRP1 is a voltage-gated potassium channel accessory subunit (beta subunit) associated with Long QT syndrome. (wikipedia.org)
- Modulation
- New compounds such as the HERG channel activator (3 R ,4 R )-4-[3-(6-methoxy-quinolin-4-yl)-3-oxo-propyl]-1-[3-(2,3,5-trifluoro-phenyl)-prop-2-ynyl]-piperidine-3-carboxylic acid (RPR260243) will enable us to increase our understanding in cation channel modulation and to test the concept of channel activation as a clinically relevant principle in treatment of channelopathies. (aspetjournals.org)
- For example, the activity of sodium channels in Paramecium tetraurelia is CaM-dependent , and CaM plays a crucial role in the modulation of calcium channels . (epfl.ch)
- regulate
- There are commonly additional regulatory domains which serve to regulate ion conduction and channel gating. (wikipedia.org)
- Because of this and its ability to regulate multiple different ion channels, KCNE2 exerts considerable influence on a number of cell types and tissues. (wikipedia.org)
- KCNE2 was originally discovered to regulate hERG channel function. (wikipedia.org)
- KCNE2 may also regulate hyperpolarization-activated, cyclic-nucleotide-gated (HCN) pacemaker channels in human heart and in the hearts of other species, as well as the Cav1.2 voltage-gated calcium channel. (wikipedia.org)
- Adrenal glucocorticoids Adrenal glucocorticoids regulate adaptation mechanisms to environmental challenges ( ) and can modify the electrical excitability of BK channels in human embryonic kidney cells. (epfl.ch)
- transmembrane voltage
- As the transmembrane voltage changes a voltage gated sodium channel opens and ions pass rapidly down an electrochemical gradient from a high concentration outside the cell through the channel pore into the cell. (bmj.com)
- The BK channel contains the transmembrane voltage sensitive domain as well as Ca2+ and Mg2+ binding. (epfl.ch)
- selective
- Channels are selective for particular ion species and can be gated, altering conformation to open or close. (bmj.com)
- Voltage-gated K+ channels are selective for K+ over other cations such as Na+. (wikipedia.org)
- Studies of a mouse model show that this disease is caused by selective loss of sodium current and excitability of GABAergic inhibitory interneurons, which leads to hyperexcitability, epilepsy, and ataxia. (jneurosci.org)
- Cation selective channels play important roles in physiological processes such as secretory transduction, control of ion homeostasis, cell volume, vesicle cycling, and electrical control of excitable tissues. (aspetjournals.org)
- Potassium-selective channels are the most genetically diverse of all cation channels. (aspetjournals.org)
- Starting with the first cloned potassium selective ion channel from Drosophila melanogaster , Shaker, more than 100 potassium channels have been identified. (aspetjournals.org)
- The S6 transmembrane segments and the S5- S6 loops form the ion selective pore, and the S4 segments contain positively charged residues conferring voltage dependence to the protein. (epfl.ch)
- channelopathies
- One might therefore expect that diseases of ion channels or channelopathies would not be compatible with life. (bmj.com)
- In a variety of channelopathies, ion channel function is reduced, and activators of cation channels are promising candidates to regain channel function in acquired or inherited channelopathies. (aspetjournals.org)
- genes
- All these genes code for ion channels. (bmj.com)
- 70%, knock-out of any of the three sodium channel α subunit genes expressed primarily in adult brain ( SCN1A , SCN2A , and SCN8A ) is lethal, demonstrating that each channel performs some nonredundant function. (jneurosci.org)
- mammalian
- The structure of the mammalian voltage-gated K+ channel has been used to explain its ability to respond to the voltage across the membrane. (wikipedia.org)
- Mammalian BK channels are characterized by their high sensitivity to blockade by iberiotoxin (IbTx) and charybdotoxin. (epfl.ch)
- pore
- They are described as minimally having two transmembrane helices flanking a loop which determines the ion selectivity of the channel pore. (wikipedia.org)
- The α subunit contains the voltage sensors and the ion-conducting pore in four internally repeated domains (I-IV), which each consists of six α-helical transmembrane segments (S1-S6) and a pore loop connecting S5 and S6 (Catterall, 2000). (jneurosci.org)
- The voltage and metal sensors all control the opening of the same ionic pore in response to various physiological signals . (epfl.ch)
- ions
- The normally negatively charged cell interior depolarises, causing voltage gated potassium channels to open and potassium ions to leave the cell, restoring the resting membrane potential. (bmj.com)
- It may seem counterintuitive that a channel should allow potassium ions but not the smaller sodium ions through. (wikipedia.org)
- In these cells, KCNQ1-KCNE2 K+ channels, which are constitutively active, provide a conduit to return K+ ions back to the stomach lumen. (wikipedia.org)
- functional
- Kvα11.x - ether-a-go-go potassium channels: Kv11.1 (KCNH2) - hERG, Kv11.2 (KCNH6), Kv11.3 (KCNH7) Kvα12.x: Kv12.1 (KCNH8), Kv12.2 (KCNH3), Kv12.3 (KCNH4) Unable to form functional channels as homotetramers but instead heterotetramerize with Kvα2 family members to form conductive channels. (wikipedia.org)
- Likewise, functional impairment of channel function might result from regulatory derangements or by autoantibodies. (aspetjournals.org)
- MiRP1
- Potassium voltage-gated channel subfamily E member 2 (KCNE2), also known as MinK-related peptide 1 (MiRP1), is a protein that in humans is encoded by the KCNE2 gene on chromosome 21. (wikipedia.org)
- intracellular
- Other factors influencing ion channel function include intracellular messengers, phosphorylation of channel residues, pH, and temperature. (bmj.com)
- BK channels are activated by voltage and intracellular Ca2+ and Mg2+. (epfl.ch)
- protein
- The high resolution crystallographic structure of the rat Kvα1.2/β2 channel has recently been solved (Protein Databank Accession Number 2A79), and then refined in a lipid membrane-like environment (PDB: 2r9r). (wikipedia.org)
- When moving through the selectivity filter of the potassium channel, the water-K+ interactions are replaced by interactions between K+ and carbonyl groups of the channel protein. (wikipedia.org)
- Hence the potassium cations are well "solvated" by the protein carbonyl groups, but these same carbonyl groups are too far apart to adequately solvate the sodium cation. (wikipedia.org)
- Voltage-gated sodium and calcium channels are closely related members of the ion channel protein superfamily ( Yu and Catterall, 2004 ). (jneurosci.org)
- Other G i/o -linked receptors that inhibit N-type Ca 2+ channels usually also activate G protein-gated inward rectifier (GIRK or Kir3) channels. (aspetjournals.org)
- The protein has multiple predicted phosphorylation sites that can modulate channel function by phosphorylation . (epfl.ch)
- The activation of protein kinase C completely suppresses the opening BK channels in intact rat anterior pituitary cells in physiological saline. (epfl.ch)
- In fact, in rat cerebellar Purkinje neurons there are multiple endogenous protein kinases and phosphatases that functionally couple to the BK channel modulating their activity. (epfl.ch)
- rectifier
- This also includes the 2-TM Inward-rectifier potassium channels (Pfam PF01007) found primarily in eukaryotes. (wikipedia.org)
- sympathetic neurons
- Individual P2Y receptors were coexpressed with GIRK1+GIRK2 (Kir3.1 + 3.2) channels by intranuclear plasmid injections into cultured rat sympathetic neurons. (aspetjournals.org)
- In previous experiments, we have sought to assess the potential neural effects of these receptors by expressing them in primary sympathetic neurons, which possess a variety of neuron-specific ion channels. (aspetjournals.org)
- aqueous
- However in an aqueous environment, potassium and sodium cations are solvated by water molecules. (wikipedia.org)
- selectivity
- They include the amino acid sequence (Thr-Val-Gly-Tyr-Gly) or (Thr-Val-Gly-Phe-Gly) typical to the selectivity filter of voltage-gated K+ channels. (wikipedia.org)
- The diameter of the selectivity filter is ideal for the potassium cation, but too big for the smaller sodium cation. (wikipedia.org)
- Hence, the passage of potassium cations through this selectivity filter is strongly favored over sodium cations. (wikipedia.org)
- KCNQ
- Recent evidence has implicated the XE991-sensitive voltage-gated K V (KCNQ) channels in the regulation of arterial tone by PVAT. (frontiersin.org)
- These channels are present in VSMCs and very potently inhibited by the KCNQ channel blocker XE991. (frontiersin.org)
- KCNQ potassium channels occur in the heart, nervous tissue, and many epithelia ( Busch and Suessbrich, 1997 ) and have important physiological functions. (aspetjournals.org)
- Sequences from various murine KCNQ-type K + channels and minK-like peptides were amplified by PCR to allow correlation of function with channel type. (aspetjournals.org)
- neurons
- Various neurotransmitters excite neurons by suppressing a ubiquitous, voltage-dependent, noninactivating K + conductance called the M-conductance (g M ). In bullfrog sympathetic ganglion neurons the suppression of g M by the P2Y agonist ATP involves phospholipase C (PLC). (jneurosci.org)
- Various pharmaceutical companies developed synthetic molecules activating these channels in order to prevent excessive neurotoxic calcium entry in neurons . (epfl.ch)
- basolateral
- KCNE2 forms constitutively active K+ channels with KCNQ1 in the basolateral membrane of thyroid epithelial cells. (wikipedia.org)
- KCNQ1-KCNE2 is required for optimal iodide uptake into the thyroid by the basolateral sodium iodide symporter (NIS). (wikipedia.org)
- The purpose of the study was to examine the interaction of XE991 with other types of K + channel, especially those in the basolateral membranes of murine epithelia. (aspetjournals.org)
- XE991 inhibited the chloride secretory current in colonic epithelia by an interaction with basolateral K + channels when forskolin was used as the stimulus. (aspetjournals.org)
- oocytes
- XE991 can also block KCNQ1 K + channels expressed in oocytes, but sensitivity is reduced when the channels are coexpressed with minK (KCNE1). (aspetjournals.org)
- gene
- Abnormalities of ion channel function are responsible for a variety of non-neurological disorders including Bartter syndrome, X linked nephrolithiasis, neonatal hyperinsulinism, long QT syndromes, and most notably defects in function of the CFTR chloride channel gene causing cystic fibrosis. (bmj.com)
- Such genetic methods allowed the genetic identification of the "Shaker" K+ channel gene in Drosophila before ion channel gene sequences were well known. (wikipedia.org)
- Na(V)1.4) encodes Nav1.4, a member of the sodium channel alpha subunit gene family. (epfl.ch)
- membrane
- Voltage-gated potassium channels (VGKCs) are transmembrane channels specific for potassium and sensitive to voltage changes in the cell's membrane potential. (wikipedia.org)
- Each subunit is composed of six membrane spanning hydrophobic α-helical sequences, as well as a voltage sensor in S1-S4. (wikipedia.org)
- Upon opening of the channel, conformational changes in the voltage-sensor domains (VSD) result in the transfer of 12-13 elementary charges across the membrane electric field. (wikipedia.org)
- Opening of vascular smooth muscle cell (VSMC) K + channels causes K + efflux and membrane hyperpolarization, which leads to reduced Ca 2+ influx though L-type Ca V 1.2 channels and consequently arterial relaxation ( Nelson and Quayle, 1995 ). (frontiersin.org)
- A sodium channel in a cell membrane whose opening is governed by the membrane potential. (epfl.ch)
- residues
- Several charged residues of the VSD, in particular four arginine residues located regularly at every third position on the S4 segment, are known to move across the transmembrane field and contribute to the gating charge. (wikipedia.org)
- physiological
- In light of the broad range of physiological roles of cation channels, it is not surprising that channel impairment results in a variety of pathophysiological conditions. (aspetjournals.org)
- complexes
- KCNE2 forms complexes there with the voltage-gated potassium channel α subunit, Kv1.3. (wikipedia.org)
- In addition, KCNE2 forms reciprocally regulating tripartite complexes in the choroid plexus epithelium with the KCNQ1 α subunit and the sodium-dependent myo-inositol transporter, SMIT1. (wikipedia.org)
- cation channel
- The transmembrane cation channel superfamily was defined in InterPro and Pfam as the family of tetrameric ion channels. (wikipedia.org)
- Shortage in cation channel activators prevents testing of efficiency of activators in a variety of indications. (aspetjournals.org)
- This shortage might result from the relative incapability of modern drug screening methods, but increasing knowledge about cation channel activator binding and action might enable us in the future to use in silico-guided drug design of channel modulators. (aspetjournals.org)
- transporter
- This large group of ion channels apparently includes families 1.A.1, 1.A.2, 1.A.3, and 1.A.4 of the TCDB transporter classification. (wikipedia.org)
- KCNQ1
- While KCNQ1 channels are inhibited by low extracellular pH, KCNQ1-KCNE2 channels activity is augmented by extracellular protons, an ideal characteristic for their role in parietal cells. (wikipedia.org)
- Presumably, if the activity of XE991 had been enhanced when KCNQ1 channels were expressed with KCNE1, the potential to cause long QT syndrome would have increased. (aspetjournals.org)
- Although the colonic tissue showed the presence of both KCNQ1 and KCNE3 mRNA, the airway epithelium also showed, uniquely, the presence of mRNA for KCNQ2. (aspetjournals.org)
- 2000
- The skeletal muscle a subunit functions as ion-conducting channel and consists of large polypeptides (1700-2000 amino acids) that fold into four highly homologous somains (repeats I-IV) containing six transmembrane segments each (S1-S6). (epfl.ch)
- activation
- BMS-204352 (BMS) was developed as a neuroprotective drug for disease conditions such as ischemic stroke and it has been shown to have a protective effect, due to activation of big-conductance calcium-activating potassium (BKCa) channels (Gribkoff et al. (epfl.ch)
- Activation or inhibition of K + channels in epithelia, particularly those secreting chloride, has potentially useful therapeutic applications in diseases as diverse as cystic fibrosis, where chloride secretion is deficient, and secretory diarrhea, where it is in excess. (aspetjournals.org)
- receptor
- Ranolazine block of open Na+ channels is via the conserved local anesthetic receptor albeit with a relatively slow on-rate. (epfl.ch)
- cell
- Nav1.4 channels are located in the sarcolemma and T-tubular membranes, with a high density near the endplate of the muscle cell. (epfl.ch)
- Current
- This charge transfer is measured as a transient capacitive current that precedes opening of the channel. (wikipedia.org)
- Our study was also aimed at extending our current knowledge on the in situ vascular pharmacology of DPO-1 and XE991 regarding K V 1.5 and BK Ca channels, in helping to identify the nature of K + channels that could contribute to PVAT-mediated relaxation. (frontiersin.org)
- The cognitive enhancer XE991 interacts with K + channels consisting of KCNQ2 and KCNQ3 heteromultimers to block the M-current. (aspetjournals.org)
- conductance
- It was found that potassium conductance highly sensitive to external TEA (1 mM ) or 4-aminopyridine (4-AP, 200 μM) is responsible for fast repolarization and afterhyperpolarization of a single AP, providing the cells with the ability for high-frequency firing. (50webs.com)
- Potassium conductance sensitive to α- dendrotoxin (α-DTX, 100 nM ) did not play such a role. (50webs.com)
- The known specificity of these drugs strongly suggested that this 4-AP and TEA-sensitive conductance is mediated by Kv3 potassium channels. (50webs.com)
- diseases
- The fruits of these collaborations include recognition that diseases caused by ion channel dysfunction may have genetic and autoimmune aetiologies. (bmj.com)
- regulation
- In this study, we tested whether K V 1.5 channels are involved in the control of mesenteric arterial tone and its regulation by PVAT. (frontiersin.org)
- Over the past decade, various potassium (K + ) channels have been implicated as important players in the regulation of arterial vascular tone and its control by perivascular adipose tissue (PVAT). (frontiersin.org)
- KCNE1
- mRNA for both these components of the cAMP-sensitive K + channels were found in high abundance in the colon, whereas KCNE1 was barely detectable. (aspetjournals.org)
- targets
- BK channels are pharmacological targets for the treatment of stroke. (epfl.ch)
- Because EBIO also activates Ca 2+ -sensitive K + channels, whereas forskolin activates only cAMP-sensitive K + channels, it is concluded that the latter are the targets for XE991. (aspetjournals.org)
- tonic
- Suppression of Ca 2+ influx through voltage-activated Ca 2+ channels by 200 μM Cd 2+ resulted mainly in moderate increase of steady-state firing frequency and increase of single AP repolarization rate, however, without abolishing the basic pattern of tonic firing. (50webs.com)
- sensitive
- However, until now the in vivo pharmacology of the involved vascular K V channels with regard to XE991 remains undetermined, since XE991 effects may involve Ca 2+ activated BK Ca channels and/or voltage-dependent K V 1.5 channels sensitive to diphenyl phosphine oxide-1 (DPO-1). (frontiersin.org)
- BK Ca channels and/or DPO-1 sensitive K V 1.5 channels in VSMCs are not the downstream mediators of the XE991 effects on PVAT-dependent arterial vasorelaxation. (frontiersin.org)
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