kcnq3 potassium channel


Summary: 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.

Top Publications

  1. Suh B, Hille B. Recovery from muscarinic modulation of M current channels requires phosphatidylinositol 4,5-bisphosphate synthesis. Neuron. 2002;35:507-20 pubmed
    ..Lipid phosphorylation by PI 4-kinase is required for recovery from muscarinic modulation of M current. ..
  2. Dickson E, Falkenburger B, Hille B. Quantitative properties and receptor reserve of the IP(3) and calcium branch of G(q)-coupled receptor signaling. J Gen Physiol. 2013;141:521-35 pubmed publisher
    ..Hence, weak PLC activation can elicit robust calcium signals without net PIP2 depletion or KCNQ2/3 channel inhibition. ..
  3. Wang H, Pan Z, Shi W, Brown B, Wymore R, Cohen I, et al. KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel. Science. 1998;282:1890-3 pubmed
    ..The biophysical properties, sensitivity to pharmacological blockade, and expression pattern of the KCNQ2 and KCNQ3 potassium channels were determined. It is concluded that both these subunits contribute to the native M-current. ..
  4. Schroeder B, Kubisch C, Stein V, Jentsch T. Moderate loss of function of cyclic-AMP-modulated KCNQ2/KCNQ3 K+ channels causes epilepsy. Nature. 1998;396:687-90 pubmed
    ..convulsions (BFNC), an autosomal dominant epilepsy of infancy, is caused by mutations in the KCNQ2 or the KCNQ3 potassium channel genes...
  5. Etxeberria A, Aivar P, Rodriguez Alfaro J, Alaimo A, Villacé P, Gómez Posada J, et al. Calmodulin regulates the trafficking of KCNQ2 potassium channels. FASEB J. 2008;22:1135-43 pubmed
    ..Thus, a direct interaction with Ca(2+)-calmodulin appears to be critical for the correct activity of KCNQ2 potassium channels as it controls the channels' exit from the ER. ..
  6. Suh B, Inoue T, Meyer T, Hille B. Rapid chemically induced changes of PtdIns(4,5)P2 gate KCNQ ion channels. Science. 2006;314:1454-7 pubmed
    ..Hence, the depletion of PI(4,5)P2 suffices to suppress current fully, and other second messengers are not needed. Our approach is ideally suited to study biological signaling networks involving membrane phosphoinositides. ..
  7. Wen H, Levitan I. Calmodulin is an auxiliary subunit of KCNQ2/3 potassium channels. J Neurosci. 2002;22:7991-8001 pubmed
    Calmodulin (CaM) was identified as a KCNQ2 and KCNQ3 potassium channel-binding protein, using a yeast two-hybrid screen...
  8. Stewart A, Gómez Posada J, McGeorge J, Rouhani M, Villarroel A, Murrell Lagnado R, et al. The Kv7.2/Kv7.3 heterotetramer assembles with a random subunit arrangement. J Biol Chem. 2012;287:11870-7 pubmed publisher
    ..Hence, there are no constraints on either the subunit stoichiometry or the subunit arrangement. ..
  9. Hadley J, Passmore G, Tatulian L, Al Qatari M, Ye F, Wickenden A, et al. Stoichiometry of expressed KCNQ2/KCNQ3 potassium channels and subunit composition of native ganglionic M channels deduced from block by tetraethylammonium. J Neurosci. 2003;23:5012-9 pubmed

More Information


  1. Pan Z, Kao T, Horvath Z, Lemos J, Sul J, Cranstoun S, et al. A common ankyrin-G-based mechanism retains KCNQ and NaV channels at electrically active domains of the axon. J Neurosci. 2006;26:2599-613 pubmed
    ..This includes the historical period when myelin also evolved. ..
  2. Shah M, Mistry M, Marsh S, Brown D, Delmas P. Molecular correlates of the M-current in cultured rat hippocampal neurons. J Physiol. 2002;544:29-37 pubmed
    ..Our data suggest that KCNQ2, KCNQ3 and KCNQ5 subunits contribute to I(K(M)) in these neurons and that the variations in TEA sensitivity may reflect differential expression of KCNQ2, KCNQ3 and KCNQ5 subunits. ..
  3. Li Y, Langlais P, Gamper N, Liu F, Shapiro M. Dual phosphorylations underlie modulation of unitary KCNQ K(+) channels by Src tyrosine kinase. J Biol Chem. 2004;279:45399-407 pubmed
    ..The implications for the mechanisms of channel regulation by the dual phosphorylations on both channel termini are discussed. ..
  4. Etxeberria A, Santana Castro I, Regalado M, Aivar P, Villarroel A. Three mechanisms underlie KCNQ2/3 heteromeric potassium M-channel potentiation. J Neurosci. 2004;24:9146-52 pubmed
  5. Oldfield S, Hancock J, Mason A, Hobson S, Wynick D, Kelly E, et al. Receptor-mediated suppression of potassium currents requires colocalization within lipid rafts. Mol Pharmacol. 2009;76:1279-89 pubmed publisher
  6. Suh B, Hille B. Does diacylglycerol regulate KCNQ channels?. Pflugers Arch. 2006;453:293-301 pubmed
  7. Wladyka C, Kunze D. KCNQ/M-currents contribute to the resting membrane potential in rat visceral sensory neurons. J Physiol. 2006;575:175-89 pubmed
    ..These data indicate that the M-current is present in nodose neurons, is activated at resting membrane potential and that it is physiologically important in regulating excitability by maintaining cells at negative voltages. ..
  8. Gómez Posada J, Etxeberria A, Roura Ferrer M, Areso P, Masin M, Murrell Lagnado R, et al. A pore residue of the KCNQ3 potassium M-channel subunit controls surface expression. J Neurosci. 2010;30:9316-23 pubmed publisher
    ..The presence of this alanine, therefore, plays an important role in regulating the subunit composition of functional M-channels expressed at the surface of neurons...
  9. Lange W, Geissendörfer J, Schenzer A, Grötzinger J, Seebohm G, Friedrich T, et al. Refinement of the binding site and mode of action of the anticonvulsant Retigabine on KCNQ K+ channels. Mol Pharmacol. 2009;75:272-80 pubmed publisher
    ..This pocket, which is formed at the interface of two adjacent subunits, may be present only in the open state of the channel, consistent with the idea that retigabine stabilizes an open-channel conformation...
  10. Tinel N, Lauritzen I, Chouabe C, Lazdunski M, Borsotto M. The KCNQ2 potassium channel: splice variants, functional and developmental expression. Brain localization and comparison with KCNQ3. FEBS Lett. 1998;438:171-6 pubmed
    ..During brain development, KCNQ3 is expressed later than KCNQ2. ..
  11. Shapiro M, Roche J, Kaftan E, Cruzblanca H, Mackie K, Hille B. Reconstitution of muscarinic modulation of the KCNQ2/KCNQ3 K(+) channels that underlie the neuronal M current. J Neurosci. 2000;20:1710-21 pubmed
    ..Our data further rule out Ca(2+) as the diffusible messenger. The reconstitution of muscarinic modulation of the M current that uses cloned components should facilitate the elucidation of the muscarinic signaling mechanism. ..
  12. Robbins J. KCNQ potassium channels: physiology, pathophysiology, and pharmacology. Pharmacol Ther. 2001;90:1-19 pubmed
    ..This review will set this family of K(+) channels amongst the other known families. It will highlight the genes, physiology, pharmacology, and pathophysiology of this recently discovered, but important, family of K(+) channels. ..
  13. Selyanko A, Hadley J, Brown D. Properties of single M-type KCNQ2/KCNQ3 potassium channels expressed in mammalian cells. J Physiol. 2001;534:15-24 pubmed
    ..By measuring these and other parameters (e.g. conductance and open probability) KCNQ2/ KCNQ3 channels can be shown to resemble previously characterised neuronal M-type channels. ..
  14. Roche J, Westenbroek R, Sorom A, Hille B, Mackie K, Shapiro M. Antibodies and a cysteine-modifying reagent show correspondence of M current in neurons to KCNQ2 and KCNQ3 K+ channels. Br J Pharmacol. 2002;137:1173-86 pubmed
    ..The site of NEM action may be important for treatment of diseases caused by under-expression of these channels. ..
  15. Schwake M, Pusch M, Kharkovets T, Jentsch T. Surface expression and single channel properties of KCNQ2/KCNQ3, M-type K+ channels involved in epilepsy. J Biol Chem. 2000;275:13343-8 pubmed
    ..Thus, the increase in currents seen upon co-expressing KCNQ2 and KCNQ3 is predominantly due to an increase in surface expression, which is dependent on an intact carboxyl terminus. ..
  16. Selyanko A, Hadley J, Wood I, Abogadie F, Jentsch T, Brown D. Inhibition of KCNQ1-4 potassium channels expressed in mammalian cells via M1 muscarinic acetylcholine receptors. J Physiol. 2000;522 Pt 3:349-55 pubmed
    ..4. It is concluded that M1 receptors couple to all known KCNQ subunits and that inhibition of KCNQ2 + KCNQ3 channels, like that of native M-channels, requires a diffusible second messenger. ..
  17. Gamper N, Shapiro M. Calmodulin mediates Ca2+-dependent modulation of M-type K+ channels. J Gen Physiol. 2003;122:17-31 pubmed
    ..We conclude that M-type currents are highly sensitive to [Ca2+]i and that calmodulin acts as their Ca2+ sensor. ..
  18. Shahidullah M, Santarelli L, Wen H, Levitan I. Expression of a calmodulin-binding KCNQ2 potassium channel fragment modulates neuronal M-current and membrane excitability. Proc Natl Acad Sci U S A. 2005;102:16454-9 pubmed
    ..These results suggest that CaM binding regulates M-channel function and membrane excitability in the native neuronal environment. ..
  19. Li Y, Gamper N, Shapiro M. Single-channel analysis of KCNQ K+ channels reveals the mechanism of augmentation by a cysteine-modifying reagent. J Neurosci. 2004;24:5079-90 pubmed
    ..To further localize the site of NEM action, we mutated three cysteine residues in the C terminus of KCNQ4. The C519A mutation alone ablated most of the augmentation by NEM, suggesting that NEM acts via alkylation of this residue. ..
  20. Brown D, Hughes S, Marsh S, Tinker A. Regulation of M(Kv7.2/7.3) channels in neurons by PIP(2) and products of PIP(2) hydrolysis: significance for receptor-mediated inhibition. J Physiol. 2007;582:917-25 pubmed
    ..Thus, inhibition by bradykinin can use product (IP(3)/Ca(2)+)-dependent or substrate (PIP(2)) dependent mechanisms, depending on Ca(2)+ availability and PIP(2) synthesis rates. ..
  21. Zaika O, Lara L, Gamper N, Hilgemann D, Jaffe D, Shapiro M. Angiotensin II regulates neuronal excitability via phosphatidylinositol 4,5-bisphosphate-dependent modulation of Kv7 (M-type) K+ channels. J Physiol. 2006;575:49-67 pubmed
    ..The results of this study establish how angioII modulates M channels, which in turn affects the integrative properties of SCG neurons. ..
  22. Falkenburger B, Dickson E, Hille B. Quantitative properties and receptor reserve of the DAG and PKC branch of G(q)-coupled receptor signaling. J Gen Physiol. 2013;141:537-55 pubmed publisher
    ..Finally, our experimental data provide indirect evidence for cleavage of PI(4)P by PLC in living cells, and our modeling revisits/explains the concept of receptor reserve with measurements from all steps of GqPCR signaling. ..
  23. Smith J, Iannotti C, Dargis P, Christian E, Aiyar J. Differential expression of kcnq2 splice variants: implications to m current function during neuronal development. J Neurosci. 2001;21:1096-103 pubmed
  24. Charlier C, Singh N, Ryan S, Lewis T, Reus B, Leach R, et al. A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family. Nat Genet. 1998;18:53-5 pubmed
    ..The same conserved amino acid is also mutated in KVLQT1 (KCNQ1) in an LQT patient. KCNQ2, KCNQ3 and undiscovered genes of the same family of K+ channels are strong candidates for other IGEs. ..
  25. Prole D, Lima P, Marrion N. Mechanisms underlying modulation of neuronal KCNQ2/KCNQ3 potassium channels by extracellular protons. J Gen Physiol. 2003;122:775-93 pubmed
    ..Contrasting modulation of homomeric KCNQ2 and KCNQ3 currents revealed that high sensitivity to H+ ions was conferred by the KCNQ3 subunit. ..
  26. Singh N, Westenskow P, Charlier C, Pappas C, Leslie J, Dillon J, et al. KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: expansion of the functional and mutation spectrum. Brain. 2003;126:2726-37 pubmed
    ..We identify 11 novel mutations in KCNQ2 and one novel mutation in the KCNQ3 potassium channel genes...
  27. Saganich M, Machado E, Rudy B. Differential expression of genes encoding subthreshold-operating voltage-gated K+ channels in brain. J Neurosci. 2001;21:4609-24 pubmed
    ..This indicates that the subthreshold current in many neurons may be complex, containing different components mediated by a number of channels with distinct properties and neuromodulatory responses. ..
  28. Tatulian L, Brown D. Effect of the KCNQ potassium channel opener retigabine on single KCNQ2/3 channels expressed in CHO cells. J Physiol. 2003;549:57-63 pubmed
    ..Thus, steady-state kinetics were modified to favour the open channel configuration...
  29. Etzioni A, Siloni S, Chikvashvilli D, Strulovich R, Sachyani D, Regev N, et al. Regulation of neuronal M-channel gating in an isoform-specific manner: functional interplay between calmodulin and syntaxin 1A. J Neurosci. 2011;31:14158-71 pubmed publisher
    ..Moreover, we show that the syntaxin 1A and calmodulin effects can be additive or blocked at different concentration ranges of calmodulin, bearing physiological significance with regard to presynaptic exocytosis. ..
  30. Hadley J, Noda M, Selyanko A, Wood I, Abogadie F, Brown D. Differential tetraethylammonium sensitivity of KCNQ1-4 potassium channels. Br J Pharmacol. 2000;129:413-5 pubmed
  31. Murata Y, Okamura Y. Depolarization activates the phosphoinositide phosphatase Ci-VSP, as detected in Xenopus oocytes coexpressing sensors of PIP2. J Physiol. 2007;583:875-89 pubmed publisher
    ..These results indicate that Ci-VSP has an activity that depletes PtdIns(4,5)P(2) unlike PTEN and that depolarization-activated voltage sensor movement is translated into activation of phosphatase activity...
  32. Wickenden A, Yu W, Zou A, Jegla T, Wagoner P. Retigabine, a novel anti-convulsant, enhances activation of KCNQ2/Q3 potassium channels. Mol Pharmacol. 2000;58:591-600 pubmed
    ..Our findings identify KCNQ2/Q3 channels as a molecular target for retigabine and suggest that activation of KCNQ2/Q3 channels may be responsible for at least some of the anticonvulsant activity of this agent...
  33. Suh B, Horowitz L, Hirdes W, Mackie K, Hille B. Regulation of KCNQ2/KCNQ3 current by G protein cycling: the kinetics of receptor-mediated signaling by Gq. J Gen Physiol. 2004;123:663-83 pubmed
    ..Further experiments will be needed to refine some untested assumptions. ..
  34. Jentsch T. Neuronal KCNQ potassium channels: physiology and role in disease. Nat Rev Neurosci. 2000;1:21-30 pubmed
    ..In addition, several KCNQ isoforms can associate to form heteromeric channels that underlie the M-current, an important regulator of neuronal excitability. ..
  35. Zhang H, Craciun L, Mirshahi T, Rohacs T, Lopes C, Jin T, et al. PIP(2) activates KCNQ channels, and its hydrolysis underlies receptor-mediated inhibition of M currents. Neuron. 2003;37:963-75 pubmed
    ..Finally, native or recombinant channels inhibited by muscarinic agonists can be activated by PIP(2). Our data strongly suggest that PIP(2) acts as a membrane-diffusible second messenger to regulate directly the activity of KCNQ currents...
  36. Gamper N, Stockand J, Shapiro M. Subunit-specific modulation of KCNQ potassium channels by Src tyrosine kinase. J Neurosci. 2003;23:84-95 pubmed
    ..Finally, experiments using cloned KCNQ2/3 channels, Src and M(1) muscarinic receptors, and sympathetic neurons demonstrated that the actions on KCNQ channels by Src and by muscarinic agonists use distinct mechanisms. ..
  37. Schwarz J, Glassmeier G, Cooper E, Kao T, Nodera H, Tabuena D, et al. KCNQ channels mediate IKs, a slow K+ current regulating excitability in the rat node of Ranvier. J Physiol. 2006;573:17-34 pubmed
    ..We conclude that the nodal I(Ks) current is mediated by KCNQ channels, which in large fibres of rat sciatic nerve appear to be KCNQ2 homomers. ..
  38. Yus Najera E, Santana Castro I, Villarroel A. The identification and characterization of a noncontinuous calmodulin-binding site in noninactivating voltage-dependent KCNQ potassium channels. J Biol Chem. 2002;277:28545-53 pubmed
    ..Thus, we propose that CaM acts as a mediator in the Ca2+-dependent modulation of KCNQ channels. ..
  39. Yus Najera E, Munoz A, Salvador N, Jensen B, Rasmussen H, Defelipe J, et al. Localization of KCNQ5 in the normal and epileptic human temporal neocortex and hippocampal formation. Neuroscience. 2003;120:353-64 pubmed
  40. Uehara A, Nakamura Y, Shioya T, Hirose S, Yasukochi M, Uehara K. Altered KCNQ3 potassium channel function caused by the W309R pore-helix mutation found in human epilepsy. J Membr Biol. 2008;222:55-63 pubmed publisher
    ..This pore-helix mutation, if occurs in the brain M channels, could thus lead to a channel dysfunction sufficient to trigger epileptic hyperexcitability. ..
  41. Hernandez C, Falkenburger B, Shapiro M. Affinity for phosphatidylinositol 4,5-bisphosphate determines muscarinic agonist sensitivity of Kv7 K+ channels. J Gen Physiol. 2009;134:437-48 pubmed publisher
    ..We were able to fully reproduce our data and extract a consistent set of PIP(2) affinities. ..
  42. Yang W, Levesque P, Little W, Conder M, Ramakrishnan P, Neubauer M, et al. Functional expression of two KvLQT1-related potassium channels responsible for an inherited idiopathic epilepsy. J Biol Chem. 1998;273:19419-23 pubmed
    ..The functional interaction between KCNQ2 and KCNQ3 provides a framework for understanding how mutations in either channel can cause a form of idiopathic generalized epilepsy. ..
  43. Martire M, Castaldo P, D Amico M, Preziosi P, Annunziato L, Taglialatela M. M channels containing KCNQ2 subunits modulate norepinephrine, aspartate, and GABA release from hippocampal nerve terminals. J Neurosci. 2004;24:592-7 pubmed
    ..These findings provide novel evidence for a major regulatory role of KCNQ2 K+ channel subunits in neurotransmitter release from rat hippocampal nerve endings...
  44. Jensen J, Lyssand J, Hague C, Hille B. Fluorescence changes reveal kinetic steps of muscarinic receptor-mediated modulation of phosphoinositides and Kv7.2/7.3 K+ channels. J Gen Physiol. 2009;133:347-59 pubmed publisher
    ..0 s) to become nearly contemporaneous with Galpha(q)/PLC interaction. Evidently, channel release of PIP(2) and closure are rapid, and the availability of active PLC limits the rate of M current suppression. ..
  45. Zaika O, Hernandez C, Bal M, Tolstykh G, Shapiro M. Determinants within the turret and pore-loop domains of KCNQ3 K+ channels governing functional activity. Biophys J. 2008;95:5121-37 pubmed publisher
  46. Wladyka C, Feng B, Glazebrook P, Schild J, Kunze D. The KCNQ/M-current modulates arterial baroreceptor function at the sensory terminal in rats. J Physiol. 2008;586:795-802 pubmed
    ..We propose that KCNQ2, KCNQ3 and KCNQ5 channels provide a hyperpolarizing influence to offset the previously described depolarizing influence of the HCN channels in baroreceptor neurons and their terminals. ..
  47. Ford C, Stemkowski P, Light P, Smith P. Experiments to test the role of phosphatidylinositol 4,5-bisphosphate in neurotransmitter-induced M-channel closure in bullfrog sympathetic neurons. J Neurosci. 2003;23:4931-41 pubmed
    ..These are the results that might be expected if agonist-induced activation of PLC and the concomitant depletion of PIP2 contribute to the excitatory action of neurotransmitters that suppress gM. ..
  48. Cooper E, Harrington E, Jan Y, Jan L. M channel KCNQ2 subunits are localized to key sites for control of neuronal network oscillations and synchronization in mouse brain. J Neurosci. 2001;21:9529-40 pubmed
    ..There is strong neuropil staining in many regions. In some instances, notably the hippocampal mossy fibers, evidence indicates this neuropil staining is presynaptic. ..
  49. Main M, Cryan J, Dupere J, Cox B, Clare J, Burbidge S. Modulation of KCNQ2/3 potassium channels by the novel anticonvulsant retigabine. Mol Pharmacol. 2000;58:253-62 pubmed
    ..Because the heteromeric KCNQ2/3 channel has recently been reported to underlie the M-current, it is likely that M-current modulation can explain the anticonvulsant actions of retigabine in animal models of epilepsy...
  50. Falkenburger B, Jensen J, Hille B. Kinetics of PIP2 metabolism and KCNQ2/3 channel regulation studied with a voltage-sensitive phosphatase in living cells. J Gen Physiol. 2010;135:99-114 pubmed publisher
    ..2010. J. Gen. Physiol. doi:10.1085/jgp.200910344), with this new information on PIP(2) synthesis and KCNQ interaction. ..
  51. Li H, Li N, Shen L, Jiang H, Yang Q, Song Y, et al. A novel mutation of KCNQ3 gene in a Chinese family with benign familial neonatal convulsions. Epilepsy Res. 2008;79:1-5 pubmed publisher
    ..c.988C>T led to the substitution Cys for Arg in amino acid position 330 (p.R330C) in KCNQ3 potassium channel, which possibly impaired the neuronal M-current and altered neuronal excitability...
  52. Yang J, Song M, Shen Y, Ryu P, Lee S. The Role of KV7.3 in Regulating Osteoblast Maturation and Mineralization. Int J Mol Sci. 2016;17:407 pubmed publisher
    ..However, activation of KV7.3 by flupirtine did not produce notable changes in matrix mineralization during osteoblast differentiation. These results suggest that KV7.3 could be a novel regulator in osteoblast differentiation. ..
  53. Dai G, Yu H, Kruse M, TRAYNOR KAPLAN A, Hille B. Osmoregulatory inositol transporter SMIT1 modulates electrical activity by adjusting PI(4,5)P2 levels. Proc Natl Acad Sci U S A. 2016;113:E3290-9 pubmed publisher
    ..We demonstrate a previously unrecognized linkage between extracellular osmotic changes and the electrical properties of excitable cells. ..