kcnq potassium channels

Summary

Summary: 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.

Top Publications

  1. Svalø J, Bille M, Parameswaran Theepakaran N, Sheykhzade M, Nordling J, Bouchelouche P. Bladder contractility is modulated by Kv7 channels in pig detrusor. Eur J Pharmacol. 2013;715:312-20 pubmed publisher
    ..Thus, we have shown that Kv7.4 channels are expressed and functionally active in pig detrusor, and that the use of selective Kv7.4 channel modulators in the treatment of detrusor overactivity seems promising. ..
  2. Soldovieri M, Miceli F, Taglialatela M. Driving with no brakes: molecular pathophysiology of Kv7 potassium channels. Physiology (Bethesda). 2011;26:365-76 pubmed publisher
    ..Here, we describe their molecular architecture, physiological roles, and involvement in genetically determined channelopathies highlighting their relevance as targets for pharmacological treatment of several human disorders. ..
  3. Maljevic S, Wuttke T, Seebohm G, Lerche H. KV7 channelopathies. Pflugers Arch. 2010;460:277-88 pubmed publisher
    ..We also assess the therapeutic potential of KV7 channels; in particular, how the activation of KV7 channels by the compounds retigabine and R-L3 may be useful for treatment of epilepsy or cardiac arrhythmia...
  4. Yeung S, Pucovsky V, Moffatt J, Saldanha L, Schwake M, Ohya S, et al. Molecular expression and pharmacological identification of a role for K(v)7 channels in murine vascular reactivity. Br J Pharmacol. 2007;151:758-70 pubmed
    ..The ion channels encoded by KCNQ genes have a crucial role in defining vascular reactivity as K(v)7 channel blockers produced marked contractions whereas K(v)7 channel activators were effective vasorelaxants. ..
  5. Tinel N, Diochot S, Borsotto M, Lazdunski M, Barhanin J. KCNE2 confers background current characteristics to the cardiac KCNQ1 potassium channel. EMBO J. 2000;19:6326-30 pubmed
    ..KCNQ1 and HERG appear to share unique interactions with KCNE1, 2 and 3 subunits. With the exception of KCNE3, mutations in all these partner subunits have been found to lead to an increased propensity for cardiac arrhythmias. ..
  6. Brickel N, Gandhi P, VanLandingham K, Hammond J, Derossett S. The urinary safety profile and secondary renal effects of retigabine (ezogabine): a first-in-class antiepileptic drug that targets KCNQ (K(v)7) potassium channels. Epilepsia. 2012;53:606-12 pubmed publisher
    ..The reported clinical effects of RTG/EZG are consistent with its documented effects on bladder smooth muscle in preclinical studies. RTG/EZG should be used with caution in patients at risk of urinary retention...
  7. Zhong X, Harhun M, Olesen S, Ohya S, Moffatt J, Cole W, et al. Participation of KCNQ (Kv7) potassium channels in myogenic control of cerebral arterial diameter. J Physiol. 2010;588:3277-93 pubmed publisher
  8. Yeung S, Greenwood I. Electrophysiological and functional effects of the KCNQ channel blocker XE991 on murine portal vein smooth muscle cells. Br J Pharmacol. 2005;146:585-95 pubmed
    ..The stimulatory effect of XE991 was not affected by the presence of 4-AP, glibenclamide nor paxilline. These data provide evidence for an important role for KCNQ channels in governing cellular excitability in mPV smooth muscle cells. ..
  9. Schenzer A, Friedrich T, Pusch M, Saftig P, Jentsch T, Grötzinger J, et al. Molecular determinants of KCNQ (Kv7) K+ channel sensitivity to the anticonvulsant retigabine. J Neurosci. 2005;25:5051-60 pubmed
    ..Transfer of the tryptophan into the KCNQ1 scaffold resulted in retigabine-sensitive heteromers, suggesting that the tryptophan is necessary in all KCNQ subunits forming a functional tetramer to confer drug sensitivity...

More Information

Publications62

  1. 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
  2. Cooper E, Jan L. M-channels: neurological diseases, neuromodulation, and drug development. Arch Neurol. 2003;60:496-500 pubmed
    ..Ongoing studies in humans and animal models will refine our understanding of KCNQ channel function and may reveal additional targets for therapeutic manipulation. ..
  3. Schwake M, Jentsch T, Friedrich T. A carboxy-terminal domain determines the subunit specificity of KCNQ K+ channel assembly. EMBO Rep. 2003;4:76-81 pubmed
    ..Conversely, a KCNQ3-sid(Q1) chimaera no longer affects KCNQ2 but interacts with KCNQ1. We conclude that the si domain suffices to determine the subunit specificity of KCNQ channel assembly. ..
  4. Bal M, Zhang J, Zaika O, Hernandez C, Shapiro M. Homomeric and heteromeric assembly of KCNQ (Kv7) K+ channels assayed by total internal reflection fluorescence/fluorescence resonance energy transfer and patch clamp analysis. J Biol Chem. 2008;283:30668-76 pubmed publisher
    ..These data confirm that among the allowed assembly conformations are KCNQ3/4 and KCNQ4/5 heteromers. ..
  5. Roza C, Lopez Garcia J. Retigabine, the specific KCNQ channel opener, blocks ectopic discharges in axotomized sensory fibres. Pain. 2008;138:537-45 pubmed publisher
    ..Results indicate that KCNQ channel opening at axotomized endings may constitute a novel and selective mechanism for modulation of some neuropathic pain symptoms...
  6. Xu T, Nie L, Zhang Y, Mo J, Feng W, Wei D, et al. Roles of alternative splicing in the functional properties of inner ear-specific KCNQ4 channels. J Biol Chem. 2007;282:23899-909 pubmed
    ..Furthermore, the dominant negative KCNQ4 mutant stifles the activity of KCNQ2-5, raising the possibility of a global disruption of KCNQ channel activity and the ensuing auditory phenotype. ..
  7. Suh B, Hille B. Regulation of KCNQ channels by manipulation of phosphoinositides. J Physiol. 2007;582:911-6 pubmed
    ..These approaches are general and can be used to test for PIP(2) requirements of other membrane proteins. ..
  8. Su C, Yang J, Shieh J, Su M, Li S. Identification of novel mutations in the KCNQ4 gene of patients with nonsyndromic deafness from Taiwan. Audiol Neurootol. 2007;12:20-6 pubmed
    ..This mutation might affect the protein structure of KCNQ4 and consequently the normal function of the K+ channel. Our data provide the first comprehensive analysis of the KCNQ4 gene in Taiwanese patients with nonsyndromic deafness. ..
  9. Tsevi I, Vicente R, Grande M, Lopez Iglesias C, Figueras A, Capella G, et al. KCNQ1/KCNE1 channels during germ-cell differentiation in the rat: expression associated with testis pathologies. J Cell Physiol. 2005;202:400-10 pubmed
    ..The presence of a K+ rich-fluid in the seminiferous tubule suggests that KCNQ1/KCNE1 is involved in K+ transport, probably during germ-cell development. ..
  10. Seebohm G, Sanguinetti M, Pusch M. Tight coupling of rubidium conductance and inactivation in human KCNQ1 potassium channels. J Physiol. 2003;552:369-78 pubmed
  11. Mustapha M, Fang Q, Gong T, Dolan D, Raphael Y, Camper S, et al. Deafness and permanently reduced potassium channel gene expression and function in hypothyroid Pit1dw mutants. J Neurosci. 2009;29:1212-23 pubmed publisher
    ..In summary, we suggest that these defects in outer hair cell and strial cell function are important contributors to the hearing impairment in Pit1(dw) mice...
  12. Orhan G, Wuttke T, Nies A, Schwab M, Lerche H. Retigabine/Ezogabine, a KCNQ/K(V)7 channel opener: pharmacological and clinical data. Expert Opin Pharmacother. 2012;13:1807-16 pubmed publisher
    ..Retigabine/Ezogabine (RTG) is a third-generation antiepileptic drug (AED) with a novel mechanism of action. It enhances the activity of voltage-gated K(V)7 potassium channels...
  13. Iannotti F, Panza E, Barrese V, Viggiano D, Soldovieri M, Taglialatela M. Expression, localization, and pharmacological role of Kv7 potassium channels in skeletal muscle proliferation, differentiation, and survival after myotoxic insults. J Pharmacol Exp Ther. 2010;332:811-20 pubmed publisher
    ..These data collectively highlight neural K(v)7 channels as significant pharmacological targets to regulate skeletal muscle proliferation, differentiation, and myotoxic effects of drugs...
  14. Seebohm G, Strutz Seebohm N, Baltaev R, Korniychuk G, Knirsch M, Engel J, et al. Regulation of KCNQ4 potassium channel prepulse dependence and current amplitude by SGK1 in Xenopus oocytes. Cell Physiol Biochem. 2005;16:255-62 pubmed
    ..In conclusion, SGK1 regulates current amplitudes and kinetic properties of KCNQ4 channel activity, an effect sensitive to mutations in the SGK1 consensus sequence of the channel. ..
  15. Joshi S, Balan P, Gurney A. Pulmonary vasoconstrictor action of KCNQ potassium channel blockers. Respir Res. 2006;7:31 pubmed
    ..This implies a functional role for KCNQ channels in regulating the resting membrane potential of pulmonary artery myocytes. ..
  16. Gurney A, Joshi S, Manoury B. KCNQ potassium channels: new targets for pulmonary vasodilator drugs?. Adv Exp Med Biol. 2010;661:405-17 pubmed publisher
    ..KCNQ channels appear to be preferentially expressed in pulmonary arteries and drugs that modulate their activity have potent effects on pulmonary artery tone. ..
  17. Ekberg J, Schuetz F, Boase N, Conroy S, Manning J, Kumar S, et al. Regulation of the voltage-gated K(+) channels KCNQ2/3 and KCNQ3/5 by ubiquitination. Novel role for Nedd4-2. J Biol Chem. 2007;282:12135-42 pubmed
    ..Furthermore, Nedd4-2 could ubiquitinate KCNQ2/3 in transfected cells. Taken together, these data suggest that Nedd4-2 is potentially an important regulator of M-current activity in the nervous system. ..
  18. Bentzen B, Schmitt N, Calloe K, Dalby Brown W, Grunnet M, Olesen S. The acrylamide (S)-1 differentially affects Kv7 (KCNQ) potassium channels. Neuropharmacology. 2006;51:1068-77 pubmed
    ..In conclusion, (S)-1 differentially affects the Kv7 channel subtypes and is dependent on a single tryptophan for the current enhancing effect in Kv7.4. ..
  19. Mencia A, González Nieto D, Modamio Høybjør S, Etxeberria A, Aránguez G, Salvador N, et al. A novel KCNQ4 pore-region mutation (p.G296S) causes deafness by impairing cell-surface channel expression. Hum Genet. 2008;123:41-53 pubmed
    ..This is the first study to identify a trafficking-dependent dominant mechanism for the loss of KCNQ4 channel function in DFNA2. ..
  20. de Heer A, Schraders M, Oostrik J, Hoefsloot L, Huygen P, Cremers C. Audioprofile-directed successful mutation analysis in a DFNA2/KCNQ4 (p.Leu274His) family. Ann Otol Rhinol Laryngol. 2011;120:243-8 pubmed
    ..Alternatively, the specially developed program AudioGene can be accessed on the Internet to perform automatic audioprofile analysis of a family's (audiological) phenotype. ..
  21. Sotty F, Damgaard T, Montezinho L, Mørk A, Olsen C, Bundgaard C, et al. Antipsychotic-like effect of retigabine [N-(2-Amino-4-(fluorobenzylamino)-phenyl)carbamic acid ester], a KCNQ potassium channel opener, via modulation of mesolimbic dopaminergic neurotransmission. J Pharmacol Exp Ther. 2009;328:951-62 pubmed publisher
    ..Taken together, our studies provide evidence that KCNQ channel openers represent a potential new class of antipsychotics. ..
  22. Melman Y, Domenech A, de la Luna S, McDonald T. Structural determinants of KvLQT1 control by the KCNE family of proteins. J Biol Chem. 2001;276:6439-44 pubmed
    ..Our results help to provide a basis for understanding the mechanism by which KCNE proteins control K(+) channel activity. ..
  23. Miceli F, Soldovieri M, Martire M, Taglialatela M. Molecular pharmacology and therapeutic potential of neuronal Kv7-modulating drugs. Curr Opin Pharmacol. 2008;8:65-74 pubmed
  24. Roura Ferrer M, Sole L, Martínez Mármol R, Villalonga N, Felipe A. Skeletal muscle Kv7 (KCNQ) channels in myoblast differentiation and proliferation. Biochem Biophys Res Commun. 2008;369:1094-7 pubmed publisher
    ..1 mRNA also increased during the G(1)-phase, pharmacological evidence mainly involves Kv7.5 in myoblast growth. Our results indicate that the cell cycle-dependent expression of Kv7.5 is involved in skeletal muscle cell proliferation. ..
  25. Huang H, Trussell L. KCNQ5 channels control resting properties and release probability of a synapse. Nat Neurosci. 2011;14:840-7 pubmed publisher
    ..Thus, ion channel determinants of presynaptic resting potential also control synaptic strength. ..
  26. Mikkelsen J. The KCNQ channel activator retigabine blocks haloperidol-induced c-Fos expression in the striatum of the rat. Neurosci Lett. 2004;362:240-3 pubmed
  27. 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. ..
  28. Vervaeke K, Gu N, Agdestein C, Hu H, Storm J. Kv7/KCNQ/M-channels in rat glutamatergic hippocampal axons and their role in regulation of excitability and transmitter release. J Physiol. 2006;576:235-56 pubmed
    ..Our results indicate that functional Kv7/KCNQ/M-channels are present in unmyelinated axons in the brain, and that these channels may have contrasting effects on excitability depending on their subcellular localization. ..
  29. Hansen H, Ebbesen C, Mathiesen C, Weikop P, Rønn L, Waroux O, et al. The KCNQ channel opener retigabine inhibits the activity of mesencephalic dopaminergic systems of the rat. J Pharmacol Exp Ther. 2006;318:1006-19 pubmed
    ..Collectively, these observations indicate that retigabine negatively modulates dopaminergic neurotransmission, likely originating from stimulation of mesencephalic KCNQ4 channels. ..
  30. Horowitz L, Hirdes W, Suh B, Hilgemann D, Mackie K, Hille B. Phospholipase C in living cells: activation, inhibition, Ca2+ requirement, and regulation of M current. J Gen Physiol. 2005;126:243-62 pubmed
    ..In each test, the suppression of KCNQ current closely paralleled the expected fall of PIP2. The results are described by a kinetic model...
  31. Brown D, Passmore G. Neural KCNQ (Kv7) channels. Br J Pharmacol. 2009;156:1185-95 pubmed publisher
    ..Flupirtine is in use as a central analgesic; retigabine is under clinical trial as a broad-spectrum anticonvulsant and is an effective analgesic in animal models of chronic inflammatory and neuropathic pain. ..
  32. Soh H, Tzingounis A. The specific slow afterhyperpolarization inhibitor UCL2077 is a subtype-selective blocker of the epilepsy associated KCNQ channels. Mol Pharmacol. 2010;78:1088-95 pubmed publisher
    ..This feature should make UCL2077 a useful tool for distinguishing KCNQ1 and KCNQ2 from less-sensitive KCNQ family members in neurons and cardiac cells in future studies. ..
  33. Abbott G, Goldstein S. Disease-associated mutations in KCNE potassium channel subunits (MiRPs) reveal promiscuous disruption of multiple currents and conservation of mechanism. FASEB J. 2002;16:390-400 pubmed
  34. Heitzmann D, Grahammer F, von Hahn T, Schmitt Gräff A, Romeo E, Nitschke R, et al. Heteromeric KCNE2/KCNQ1 potassium channels in the luminal membrane of gastric parietal cells. J Physiol. 2004;561:547-57 pubmed
    ..IKs124 could serve as a leading compound in the development of subunit-specific KCNE2/KCNQ1 blockers to treat peptic ulcers...
  35. 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
  36. Cavaliere S, Hodge J. Drosophila KCNQ channel displays evolutionarily conserved electrophysiology and pharmacology with mammalian KCNQ channels. PLoS ONE. 2011;6:e23898 pubmed publisher
  37. Caminos E, Garcia Pino E, Martinez Galan J, Juiz J. The potassium channel KCNQ5/Kv7.5 is localized in synaptic endings of auditory brainstem nuclei of the rat. J Comp Neurol. 2007;505:363-78 pubmed
    ..These findings predict pre- and postsynaptic roles for KCNQ5 in excitability regulation in auditory brainstem nuclei, at the level of glutamatergic excitatory endings and in dendrites. ..
  38. De Leenheer E, Huygen P, Coucke P, Admiraal R, Van Camp G, Cremers C. Longitudinal and cross-sectional phenotype analysis in a new, large Dutch DFNA2/KCNQ4 family. Ann Otol Rhinol Laryngol. 2002;111:267-74 pubmed
    ..Persons with this KCNQ4 mutation showed congenital, progressive high-frequency impairment without substantial loss of speech recognition during the first decades of life. ..
  39. Melman Y, Um S, Krumerman A, Kagan A, McDonald T. KCNE1 binds to the KCNQ1 pore to regulate potassium channel activity. Neuron. 2004;42:927-37 pubmed
    ..Specific gating control is localized to a single site of interaction between the ion channel and accessory subunit. Thus, direct physical interaction with the ion channel pore is the basis of KCNE1 regulation of K+ channels. ..
  40. Beisel K, Rocha Sanchez S, Morris K, Nie L, Feng F, Kachar B, et al. Differential expression of KCNQ4 in inner hair cells and sensory neurons is the basis of progressive high-frequency hearing loss. J Neurosci. 2005;25:9285-93 pubmed
    ..Progressive hearing loss associated with aging may result from an increasing mutational load expansion toward the apex in inner hair cells and spiral ganglion neurons...
  41. Gao Y, Yechikov S, Vazquez A, Chen D, Nie L. Distinct roles of molecular chaperones HSP90? and HSP90? in the biogenesis of KCNQ4 channels. PLoS ONE. 2013;8:e57282 pubmed publisher
    ..KCNQ4 surface expression was restored by HSP90? in cells mimicking heterozygous conditions of the DFNA2 patients, even though it was not sufficient to rescue the function of KCNQ4 channels. ..
  42. Chambard J, Ashmore J. Regulation of the voltage-gated potassium channel KCNQ4 in the auditory pathway. Pflugers Arch. 2005;450:34-44 pubmed
    ..We suggest that KCNQ4 phosphorylation via PKA and coupling to a complex that may include prestin can lead to the negative activation and the negative resting potential found in adult OHCs. ..
  43. Tapper A, George A. MinK subdomains that mediate modulation of and association with KvLQT1. J Gen Physiol. 2000;116:379-90 pubmed
    ..The results from this analysis indicate that MiRP1 cannot modulate KvLQT1 due to differences within the transmembrane domain. Our results allow us to identify the MinK subdomains that mediate KvLQT1 association and modulation. ..
  44. Lerche C, Seebohm G, Wagner C, Scherer C, Dehmelt L, Abitbol I, et al. Molecular impact of MinK on the enantiospecific block of I(Ks) by chromanols. Br J Pharmacol. 2000;131:1503-6 pubmed
    ..5 fold). This could indicate that MinK does not directly take part in chromanol binding but acts allosterically to facilitate drug binding to the principal subunit KCNQ1. ..
  45. Rode F, Svalø J, Sheykhzade M, Rønn L. Functional effects of the KCNQ modulators retigabine and XE991 in the rat urinary bladder. Eur J Pharmacol. 2010;638:121-7 pubmed publisher
    ..In conclusion, this study demonstrates an efficacious KCNQ dependent effect of retigabine and XE991 on rat bladder contractility...
  46. Jepps T, Greenwood I, Moffatt J, Sanders K, Ohya S. Molecular and functional characterization of Kv7 K+ channel in murine gastrointestinal smooth muscles. Am J Physiol Gastrointest Liver Physiol. 2009;297:G107-15 pubmed publisher
    ..Drugs that selectively block K(v)7.4/7.5 might be promising therapeutics for the treatment of motility disorders such as constipation associated with irritable bowel syndrome...
  47. Yeung S, Schwake M, Pucovsky V, Greenwood I. Bimodal effects of the Kv7 channel activator retigabine on vascular K+ currents. Br J Pharmacol. 2008;155:62-72 pubmed publisher
    ..This study investigated the functional and electrophysiological effects of the Kv7 channel activator, retigabine, on murine portal vein smooth muscle...
  48. Brown D. Kv7 (KCNQ) potassium channels that are mutated in human diseases. J Physiol. 2008;586:1781-3 pubmed publisher
  49. 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
    ..In this study we examined the contribution of KCNQ potassium channels that underlie the M-current to the function of the arterial baroreceptors...
  50. 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. ..
  51. Stern R, Lalwani A. Audiologic evidence for further genetic heterogeneity at DFNA2. Acta Otolaryngol. 2002;122:730-5 pubmed
    ..Therefore, this family provides clinical evidence of genetic heterogeneity at the DFNA2 locus and can serve as a model for age-related hearing loss. ..
  52. Wuttke T, Seebohm G, Bail S, Maljevic S, Lerche H. The new anticonvulsant retigabine favors voltage-dependent opening of the Kv7.2 (KCNQ2) channel by binding to its activation gate. Mol Pharmacol. 2005;67:1009-17 pubmed
    ..We propose that RTG binds to a hydrophobic pocket formed upon channel opening between the cytoplasmic parts of S5 and S6 involving Trp236 and the channel's gate, which could well explain the strong shift in voltage-dependent activation...
  53. Xiong Q, Gao Z, Wang W, Li M. Activation of Kv7 (KCNQ) voltage-gated potassium channels by synthetic compounds. Trends Pharmacol Sci. 2008;29:99-107 pubmed publisher
    ..Recent advances in defining the activator-binding sites and in understanding their mechanism of action have begun to provide insight into the activation of voltage-gated channels by synthetic compounds. ..