Abstract
Kv7.1-Kv7.5 (KCNQ1–5) K+ channels are voltage-gated K+ channels with major roles in neurons, muscle cells and epithelia where they underlie physiologically important K+ currents, such as neuronal M current and cardiac IKs. Specific biophysical properties of Kv7 channels make them particularly well placed to control the activity of excitable cells. Indeed, these channels often work as ‘excitability breaks’ and are targeted by various hormones and modulators to regulate cellular activity outputs. Genetic deficiencies in all five KCNQ genes result in human excitability disorders, including epilepsy, arrhythmias, deafness and some others. Not surprisingly, this channel family attracts considerable attention as potential drug targets. Here we will review biophysical properties and tissue expression profile of Kv7 channels, discuss recent advances in the understanding of their structure as well as their role in various neurological, cardiovascular and other diseases and pathologies. We will also consider a scope for therapeutic targeting of Kv7 channels for treatment of the above health conditions.
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References
Abbott GW (2016) Novel exon 1 protein-coding regions N-terminally extend human KCNE3 and KCNE4. FASEB J 30:2959–2969
Abbott GW (2020) KCNQs: ligand- and voltage-gated potassium channels. Front Physiol 11:583
Adduci A, Martire M, Taglialatela M, Arena V, Rizzo G, Coco C, Currò D (2013) Expression and motor functional roles of voltage-dependent type 7 K(+) channels in the human taenia coli. Eur J Pharmacol 721:12–20
Afeli SA, Malysz J, Petkov GV (2013) Molecular expression and pharmacological evidence for a functional role of kv7 channel subtypes in Guinea pig urinary bladder smooth muscle. PLoS One 8:e75875
Aiken SP, Lampe BJ, Murphy PA, Brown BS (1995) Reduction of spike frequency adaptation and blockade of M-current in rat CA1 pyramidal neurones by linopirdine (DuP 996), a neurotransmitter release enhancer. Br J Pharmacol 115:1163–1168
Anderson UA, Carson C, Johnston L, Joshi S, Gurney AM, McCloskey KD (2013) Functional expression of KCNQ (Kv7) channels in Guinea pig bladder smooth muscle and their contribution to spontaneous activity. Br J Pharmacol 169:1290–1304
Angelo K, Jespersen T, Grunnet M, Nielsen MS, Klaerke DA, Olesen SP (2002) KCNE5 induces time- and voltage-dependent modulation of the KCNQ1 current. Biophys J 83:1997–2006
Antzelevitch C, Burashnikov A (2011) Overview of basic mechanisms of cardiac arrhythmia. Card Electrophysiol Clin 3:23–45
Archer CR, Enslow BT, Taylor AB, De la Rosa V, Bhattacharya A, Shapiro MS (2019) A mutually induced conformational fit underlies ca(2+)-directed interactions between calmodulin and the proximal C terminus of KCNQ4 K(+) channels. J Biol Chem 294:6094–6112
Arnsten AFT, Jin LE, Gamo NJ, Ramos B, Paspalas CD, Morozov YM, Kata A, Bamford NS, Yeckel MF, Kaczmarek LK, El-Hassar L (2019) Role of KCNQ potassium channels in stress-induced deficit of working memory. Neurobiol Stress 11:100187
Bal M, Zhang J, Zaika O, Hernandez CC, Shapiro MS (2008) 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 283:30668–30676
Bal M, Zhang J, Hernandez CC, Zaika O, Shapiro MS (2010) Ca2+/calmodulin disrupts AKAP79/150 interactions with KCNQ (M-type) K+ channels. J Neurosci 30:2311–2323
Barhanin J, Lesage F, Guillemare E, Fink M, Lazdunski M, Romey G (1996) K(V)LQT1 and lsK (minK) proteins associate to form the I(Ks) cardiac potassium current. Nature 384:78–80
Barnes PJ (1986) Asthma as an axon reflex. Lancet 1:242–245
Barrese V, Stott JB, Figueiredo HB, Aubdool AA, Hobbs AJ, Jepps TA, McNeish AJ, Greenwood IA (2018) Angiotensin II promotes KV7.4 channels degradation through reduced interaction with HSP90 (heat shock protein 90). Hypertension 71:1091–1100
Barro-Soria R, Rebolledo S, Liin SI, Perez ME, Sampson KJ, Kass RS, Larsson HP (2014) KCNE1 divides the voltage sensor movement in KCNQ1/KCNE1 channels into two steps. Nat Commun 5:3750
Bartos DC, Giudicessi JR, Tester DJ, Ackerman MJ, Ohno S, Horie M, Gollob MH, Burgess DE, Delisle BP (2014) A KCNQ1 mutation contributes to the concealed type 1 long QT phenotype by limiting the Kv7.1 channel conformational changes associated with protein kinase A phosphorylation. Heart Rhythm 11:459–468
Beisel KW, Nelson NC, Delimont DC, Fritzsch B (2000) Longitudinal gradients of KCNQ4 expression in spiral ganglion and cochlear hair cells correlate with progressive hearing loss in DFNA2. Brain Res Mol Brain Res 82:137–149
Bellocq C, van Ginneken AC, Bezzina CR, Alders M, Escande D, Mannens MM, Baro I, Wilde AA (2004) Mutation in the KCNQ1 gene leading to the short QT-interval syndrome. Circulation 109:2394–2397
Bendahhou S, Marionneau C, Haurogne K, Larroque MM, Derand R, Szuts V, Escande D, Demolombe S, Barhanin J (2005) In vitro molecular interactions and distribution of KCNE family with KCNQ1 in the human heart. Cardiovasc Res 67:529–538
Bernardo-Seisdedos G, Nunez E, Gomis-Perez C, Malo C, Villarroel A, Millet O (2018) Structural basis and energy landscape for the ca(2+) gating and calmodulation of the Kv7.2 K(+) channel. Proc Natl Acad Sci U S A 115:2395–2400
Biervert C, Schroeder BC, Kubisch C, Berkovic SF, Propping P, Jentsch TJ, Steinlein OK (1998) A potassium channel mutation in neonatal human epilepsy. Science 279:403–406
Bleich M, Warth R (2000) The very small-conductance K+ channel KvLQT1 and epithelial function. Pflugers Arch 440:202–206
Brown DA, Adams PR (1980) Muscarinic suppression of a novel voltage-sensitive K+ current in a vertebrate neurone. Nature 283:673–676
Brown DA, Passmore GM (2009) Neural KCNQ (Kv7) channels. Br J Pharmacol 156:1185–1195
Brown DA, Abogadie FC, Allen TG, Buckley NJ, Caulfield MP, Delmas P, Haley JE, Lamas JA, Selyanko AA (1997) Muscarinic mechanisms in nerve cells. Life Sci 60:1137–1144
Brown DA, Hughes SA, Marsh SJ, Tinker A (2007) 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 582:917–925
Brueggemann LI, Moran CJ, Barakat JA, Yeh JZ, Cribbs LL, Byron KL (2007) Vasopressin stimulates action potential firing by protein kinase C-dependent inhibition of KCNQ5 in A7r5 rat aortic smooth muscle cells. Am J Physiol Heart Circ Physiol 292:H1352–H1363
Brueggemann LI, Kakad PP, Love RB, Solway J, Dowell ML, Cribbs LL, Byron KL (2012) Kv7 potassium channels in airway smooth muscle cells: signal transduction intermediates and pharmacological targets for bronchodilator therapy. Am J Physiol Lung Cell Mol Physiol 302:L120–L132
Brueggemann LI, Haick JM, Neuburg S, Tate S, Randhawa D, Cribbs LL, Byron KL (2014a) KCNQ (Kv7) potassium channel activators as bronchodilators: combination with a beta2-adrenergic agonist enhances relaxation of rat airways. Am J Physiol Lung Cell Mol Physiol 306:L476–L486
Brueggemann LI, Haick JM, Neuburg S, Tate S, Randhawa D, Cribbs LL, Byron KL (2014b) KCNQ (Kv7) potassium channel activators as bronchodilators: combination with a β2-adrenergic agonist enhances relaxation of rat airways. Am J Physiol Lung Cell Mol Physiol 306:L476–L486
Brueggemann LI, Mackie AR, Cribbs LL, Freda J, Tripathi A, Majetschak M, Byron KL (2014c) Differential protein kinase C-dependent modulation of Kv7.4 and Kv7.5 subunits of vascular Kv7 channels. J Biol Chem 289:2099–2111
Brueggemann LI, Cribbs LL, Schwartz J, Wang M, Kouta A, Byron KL (2018) Mechanisms of PKA-dependent potentiation of Kv7.5 channel activity in human airway smooth muscle cells. Int J Mol Sci:19
Burgess DE, Bartos DC, Reloj AR, Campbell KS, Johnson JN, Tester DJ, Ackerman MJ, Fressart V, Denjoy I, Guicheney P, Moss AJ, Ohno S, Horie M, Delisle BP (2012) High-risk long QT syndrome mutations in the Kv7.1 (KCNQ1) pore disrupt the molecular basis for rapid K(+) permeation. Biochemistry 51:9076–9085
Busch AE, Busch GL, Ford E, Suessbrich H, Lang HJ, Greger R, Kunzelmann K, Attali B, Stuhmer W (1997) The role of the IsK protein in the specific pharmacological properties of the IKs channel complex. Br J Pharmacol 122:187–189
Cannady R, Rinker JA, Nimitvilai S, Woodward JJ, Mulholland PJ (2018) Chronic alcohol, intrinsic excitability, and potassium channels: neuroadaptations and drinking behavior. Handbook Exp Pharmacol 248:311–343
Carignano C, Barila EP, Rias EI, Dionisio L, Aztiria E, Spitzmaul G (2019) Inner hair cell and neuron degeneration contribute to hearing loss in a DFNA2-like mouse model. Neuroscience 410:202–216
Cavaliere S, Malik BR, Hodge JJ (2013) KCNQ channels regulate age-related memory impairment. PLoS One 8:e62445
Chadha PS, Zunke F, Zhu HL, Davis AJ, Jepps TA, Olesen SP, Cole WC, Moffatt JD, Greenwood IA (2012) Reduced KCNQ4-encoded voltage-dependent potassium channel activity underlies impaired beta-adrenoceptor-mediated relaxation of renal arteries in hypertension. Hypertension 59:877–884
Chadha PS, Jepps TA, Carr G, Stott JB, Zhu HL, Cole WC, Greenwood IA (2014) Contribution of kv7.4/kv7.5 heteromers to intrinsic and calcitonin gene-related peptide-induced cerebral reactivity. Arterioscler Thromb Vasc Biol 34:887–893
Chandrasekhar KD, Lvov A, Terrenoire C, Gao GY, Kass RS, Kobertz WR (2011) O-glycosylation of the cardiac I(Ks) complex. J Physiol 589:3721–3730
Chang A, Abderemane-Ali F, Hura GL, Rossen ND, Gate RE, Minor DL Jr (2018) A calmodulin C-lobe ca(2+)-dependent switch governs Kv7 channel function. Neuron 97:836–852.e6
Charlier C, Singh NA, Ryan SG, Lewis TB, Reus BE, Leach RJ, Leppert M (1998) A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family. Nat Genet 18:53–55
Chen YH, Xu SJ, Bendahhou S, Wang XL, Wang Y, Xu WY, Jin HW, Sun H, Su XY, Zhuang QN, Yang YQ, Li YB, Liu Y, Xu HJ, Li XF, Ma N, Mou CP, Chen Z, Barhanin J, Huang W (2003) KCNQ1 gain-of-function mutation in familial atrial fibrillation. Science 299:251–254
Choi SY, Kim HR, Ryu PD, Lee SY (2017) Regulation of voltage-gated potassium channels attenuates resistance of side-population cells to gefitinib in the human lung cancer cell line NCI-H460. BMC Pharmacol Toxicol 18:14
Choveau FS, Shapiro MS (2012) Regions of KCNQ K(+) channels controlling functional expression. Front Physiol 3:397
Choveau FS, De la Rosa V, Bierbower SM, Hernandez CC, Shapiro MS (2018) Phosphatidylinositol 4,5-bisphosphate (PIP2) regulates KCNQ3 K(+) channels by interacting with four cytoplasmic channel domains. J Biol Chem 293:19411–19428
Chung HJ, Jan YN, Jan LY (2006) Polarized axonal surface expression of neuronal KCNQ channels is mediated by multiple signals in the KCNQ2 and KCNQ3 C-terminal domains. Proc Natl Acad Sci U S A 103:8870–8875
Constanti A, Brown DA (1981) M-currents in voltage-clamped mammalian sympathetic neurones. Neurosci Lett 24:289–294
Cooper EC (2011) Made for "anchorin": Kv7.2/7.3 (KCNQ2/KCNQ3) channels and the modulation of neuronal excitability in vertebrate axons. Semin Cell Dev Biol 22:185–192
Cooper EC, Harrington E, Jan YN, Jan LY (2001) M channel KCNQ2 subunits are localized to key sites for control of neuronal network oscillations and synchronization in mouse brain. J Neurosci 21:9529–9540
Coucke PJ, Hauwe PV, Kelley PM, Kunst H, Schatteman I, Velzen DV, Meyers J, Ensink RJ, Verstreken M, Declau F, Marres H, Kastury K, Bhasin S, McGuirt WT, Smith RJ, Cremers CW, Heyning PV, Willems PJ, Smith SD, Camp GV (1999) Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families. Hum Mol Genet 8:1321–1328
Crozier RA, Ajit SK, Kaftan EJ, Pausch MH (2007) MrgD activation inhibits KCNQ/M-currents and contributes to enhanced neuronal excitability. J Neurosci 27:4492–4496
Cruzblanca H, Koh DS, Hille B (1998) Bradykinin inhibits M current via phospholipase C and Ca2+ release from IP3-sensitive Ca2+ stores in rat sympathetic neurons. Proc Natl Acad Sci U S A 95:7151–7156
Currò D (2014) K+ channels as potential targets for the treatment of gastrointestinal motor disorders. Eur J Pharmacol 733:97–101
Dahimene S, Alcolea S, Naud P, Jourdon P, Escande D, Brasseur R, Thomas A, Baro I, Merot J (2006) The N-terminal juxtamembranous domain of KCNQ1 is critical for channel surface expression: implications in the Romano-Ward LQT1 syndrome. Circ Res 99:1076–1083
Dedek K, Waldegger S (2001) Colocalization of KCNQ1/KCNE channel subunits in the mouse gastrointestinal tract. Pflugers Arch 442:896–902
Delmas P, Brown DA (2005) Pathways modulating neural KCNQ/M (Kv7) potassium channels. Nat Rev Neurosci 6:850–862
Demolombe S, Franco D, de Boer P, Kuperschmidt S, Roden D, Pereon Y, Jarry A, Moorman AF, Escande D (2001) Differential expression of KvLQT1 and its regulator IsK in mouse epithelia. Am J Physiol Cell Physiol 280:C359–C372
Du X, Gamper N (2013) Potassium channels in peripheral pain pathways: expression, function and therapeutic potential. Curr Neuropharmacol 11:621–640
Du X, Gao H, Jaffe D, Zhang H, Gamper N (2018) M-type K+ channels in peripheral nociceptive pathways. Br J Pharmacol 175:2158–2172
Dvir M, Strulovich R, Sachyani D, Ben-Tal Cohen I, Haitin Y, Dessauer C, Pongs O, Kass R, Hirsch JA, Attali B (2014) Long QT mutations at the interface between KCNQ1 helix C and KCNE1 disrupt I(KS) regulation by PKA and PIP(2). J Cell Sci 127:3943–3955
Ekberg J, Schuetz F, Boase NA, Conroy SJ, Manning J, Kumar S, Poronnik P, Adams DJ (2007) Regulation of the voltage-gated K(+) channels KCNQ2/3 and KCNQ3/5 by ubiquitination. Novel role for Nedd4-2. J Biol Chem 282:12135–12142
Etxeberria A, Aivar P, Rodriguez-Alfaro JA, Alaimo A, Villace P, Gomez-Posada JC, Areso P, Villarroel A (2008) Calmodulin regulates the trafficking of KCNQ2 potassium channels. FASEB J 22:1135–1143
Etzioni A, Siloni S, Chikvashvilli D, Strulovich R, Sachyani D, Regev N, Greitzer-Antes D, Hirsch JA, Lotan I (2011) Regulation of neuronal M-channel gating in an isoform-specific manner: functional interplay between calmodulin and Syntaxin 1A. J Neurosci 31:14158–14171
Evseev AI, Semenov I, Archer CR, Medina JL, Dube PH, Shapiro MS, Brenner R (2013) Functional effects of KCNQ K(+) channels in airway smooth muscle. Front Physiol 4:277
Fedorenko O, Strutz-Seebohm N, Henrion U, Ureche ON, Lang F, Seebohm G, Lang UE (2008) A schizophrenia-linked mutation in PIP5K2A fails to activate neuronal M channels. Psychopharmacology 199:47–54
Fedorenko O, Rudikov EV, Gavrilova VA, Boiarko EG, Semke AV, Ivanova SA (2013) Association of (N251S)-PIP5K2A with schizophrenic disorders: a study of the Russian population of Siberia. Zh Nevrol Psikhiatr Im S S Korsakova 113:58–61
Feng M, Crowley NA, Patel A, Guo Y, Bugni SE, Luscher B (2019) Reversal of a treatment-resistant, depression-related brain state with the Kv7 channel opener Retigabine. Neuroscience 406:109–125
Filippov AK, Choi RC, Simon J, Barnard EA, Brown DA (2006) Activation of P2Y1 nucleotide receptors induces inhibition of the M-type K+ current in rat hippocampal pyramidal neurons. J Neurosci 26:9340–9348
Ford CP, Stemkowski PL, Light PE, Smith PA (2003) Experiments to test the role of phosphatidylinositol 4,5-bisphosphate in neurotransmitter-induced M-channel closure in bullfrog sympathetic neurons. J Neurosci 23:4931–4941
Ford CP, Stemkowski PL, Smith PA (2004) Possible role of phosphatidylinositol 4,5 bisphosphate in luteinizing hormone releasing hormone-mediated M-current inhibition in bullfrog sympathetic neurons. Eur J Neurosci 20:2990–2998
Fosmo AL, Skraastad OB (2017) The Kv7 channel and cardiovascular risk factors. Front Cardiovasc Med 4:75
Frankel S, Medvedeva N, Gutherz S, Kulick C, Kondratyev A, Forcelli PA (2016) Comparison of the long-term behavioral effects of neonatal exposure to retigabine or phenobarbital in rats. Epilepsy Behav E&B 57:34–40
Friedman AK, Juarez B, Ku SM, Zhang H, Calizo RC, Walsh JJ, Chaudhury D, Zhang S, Hawkins A, Dietz DM, Murrough JW, Ribadeneira M, Wong EH, Neve RL, Han MH (2016) KCNQ channel openers reverse depressive symptoms via an active resilience mechanism. Nat Commun 7:11671
Gamper N, Rohacs T (2012) Phosphoinositide sensitivity of ion channels, a functional perspective. Subcell Biochem 59:289–333
Gamper N, Shapiro MS (2003) Calmodulin mediates Ca2+−dependent modulation of M-type K+ channels. J Gen Physiol 122:17–31
Gamper N, Shapiro MS (2007) Regulation of ion transport proteins by membrane phosphoinositides. Nat Rev Neurosci 8:921–934
Gamper N, Shapiro MS (2015) KCNQ channels. In: Zheng J, Trudeau MC (eds) Handbook of ion channels. CRC Press, Boca Raton, pp 275–306
Gamper N, Stockand JD, Shapiro MS (2003) Subunit-specific modulation of KCNQ potassium channels by Src tyrosine kinase. J Neurosci 23:84–95
Gamper N, Li Y, Shapiro MS (2005) Structural requirements for differential sensitivity of KCNQ K+ channels to modulation by Ca2+/calmodulin. Mol Biol Cell 16:3538–3551
Gamper N, Zaika O, Li Y, Martin P, Hernandez CC, Perez MR, Wang AY, Jaffe DB, Shapiro MS (2006) Oxidative modification of M-type K(+) channels as a mechanism of cytoprotective neuronal silencing. EMBO J 25:4996–5004
Gao Y, Yechikov S, Vazquez AE, Chen D, Nie L (2013) Impaired surface expression and conductance of the KCNQ4 channel lead to sensorineural hearing loss. J Cell Mol Med 17:889–900
Gao HX, Boillat A, Huang DY, Liang C, Peers C, Gamper N (2017) Intracellular zinc activates KCNQ channels by reducing their dependence on phosphatidylinositol 4,5-bisphosphate. Proc Natl Acad Sci U S A 114:E6410–E6419
Geiger J, Weber YG, Landwehrmeyer B, Sommer C, Lerche H (2006) Immunohistochemical analysis of KCNQ3 potassium channels in mouse brain. Neurosci Lett 400:101–104
Geisheker MR, Heymann G, Wang T, Coe BP, Turner TN, Stessman HAF, Hoekzema K, Kvarnung M, Shaw M, Friend K, Liebelt J, Barnett C, Thompson EM, Haan E, Guo H, Anderlid BM, Nordgren A, Lindstrand A, Vandeweyer G, Alberti A, Avola E, Vinci M, Giusto S, Pramparo T, Pierce K, Nalabolu S, Michaelson JJ, Sedlacek Z, Santen GWE, Peeters H, Hakonarson H, Courchesne E, Romano C, Kooy RF, Bernier RA, Nordenskjöld M, Gecz J, Xia K, Zweifel LS, Eichler EE (2017) Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains. Nat Neurosci 20:1043–1051
Ghosh S, Nunziato DA, Pitt GS (2006) KCNQ1 assembly and function is blocked by long-QT syndrome mutations that disrupt interaction with calmodulin. Circ Res 98:1048–1054
Girault A, Privé A, Trinh NT, Bardou O, Ferraro P, Joubert P, Bertrand R, Brochiero E (2014) Identification of KvLQT1 K+ channels as new regulators of non-small cell lung cancer cell proliferation and migration. Int J Oncol 44:838–848
Grahammer F, Herling AW, Lang HJ, Schmitt-Graff A, Wittekindt OH, Nitschke R, Bleich M, Barhanin J, Warth R (2001) The cardiac K+ channel KCNQ1 is essential for gastric acid secretion. Gastroenterology 120:1363–1371
Greene DL, Hoshi N (2017) Modulation of Kv7 channels and excitability in the brain. Cell Mol Life Sci 74:495–508
Grunnet M, Jespersen T, Rasmussen HB, Ljungstrom T, Jorgensen NK, Olesen SP, Klaerke DA (2002) KCNE4 is an inhibitory subunit to the KCNQ1 channel. J Physiol 542:119–130
Grunnet M, Jespersen T, MacAulay N, Jorgensen NK, Schmitt N, Pongs O, Olesen SP, Klaerke DA (2003) KCNQ1 channels sense small changes in cell volume. J Physiol 549:419–427
Grunnet M, Olesen SP, Klaerke DA, Jespersen T (2005) hKCNE4 inhibits the hKCNQ1 potassium current without affecting the activation kinetics. Biochem Biophys Res Commun 328:1146–1153
Grunnet M, Strøbæk D, Hougaard C, Christophersen P (2014) Kv7 channels as targets for anti-epileptic and psychiatric drug-development. Eur J Pharmacol 726:133–137
Grupe M, Bentzen BH, Benned-Jensen T, Nielsen V, Frederiksen K, Jensen HS, Jacobsen AM, Skibsbye L, Sams AG, Grunnet M, Rottländer M, Bastlund JF (2020) In vitro and in vivo characterization of Lu AA41178: a novel, brain penetrant, pan-selective Kv7 potassium channel opener with efficacy in preclinical models of epileptic seizures and psychiatric disorders. Eur J Pharmacol:173440
Haick JM, Brueggemann LI, Cribbs LL, Denning MF, Schwartz J, Byron KL (2017) PKC-dependent regulation of Kv7.5 channels by the bronchoconstrictor histamine in human airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 312:L822–L834
Haitin Y, Attali B (2008) The C-terminus of Kv7 channels: a multifunctional module. J Physiol 586:1803–1810
Hamilton KL, Devor DC (2012) Basolateral membrane K+ channels in renal epithelial cells. Am J Physiol Renal Physiol 302:F1069–F1081
Hammami Bomholtz S, Refaat M, Buur Steffensen A, David JP, Espinosa K, Nussbaum R, Wojciak J, Hjorth Bentzen B, Scheinman M, Schmitt N (2020) Functional phenotype variations of two novel KV 7.1 mutations identified in patients with long QT syndrome. Pacing Clin Electrophysiol 43:210–216
Hansen HH, Andreasen JT, Weikop P, Mirza N, Scheel-Krüger J, Mikkelsen JD (2007) The neuronal KCNQ channel opener retigabine inhibits locomotor activity and reduces forebrain excitatory responses to the psychostimulants cocaine, methylphenidate and phencyclidine. Eur J Pharmacol 570:77–88
He Z, Li Z, Shi Y, Tang W, Huang K, Ma G, Zhou J, Meng J, Li H, Feng G, He L (2007) The PIP5K2A gene and schizophrenia in the Chinese population--a case-control study. Schizophr Res 94:359–365
Hedegaard ER, Nielsen BD, Kun A, Hughes AD, Kroigaard C, Mogensen S, Matchkov VV, Frobert O, Simonsen U (2014) KV 7 channels are involved in hypoxia-induced vasodilatation of porcine coronary arteries. Br J Pharmacol 171:69–82
Heidenreich M, Lechner SG, Vardanyan V, Wetzel C, Cremers CW, de Leenheer EM, Aranguez G, Moreno-Pelayo MA, Jentsch TJ, Lewin GR (2012) KCNQ4 K(+) channels tune mechanoreceptors for normal touch sensation in mouse and man. Nat Neurosci 15:138–145
Heitzmann D, Grahammer F, von Hahn T, Schmitt-Gräff A, Romeo E, Nitschke R, Gerlach U, Lang HJ, Verrey F, Barhanin J, Warth R (2004) Heteromeric KCNE2/KCNQ1 potassium channels in the luminal membrane of gastric parietal cells. J Physiol 561:547–557
Hernandez CC, Zaika O, Shapiro MS (2008a) A carboxy-terminal inter-helix linker as the site of phosphatidylinositol 4,5-bisphosphate action on Kv7 (M-type) K+ channels. J Gen Physiol 132:361–381
Hernandez CC, Zaika O, Tolstykh GP, Shapiro MS (2008b) Regulation of neural KCNQ channels: signalling pathways, structural motifs and functional implications. J Physiol 586:1811–1821
Higashida H, Hoshi N, Zhang JS, Yokoyama S, Hashii M, Jin D, Noda M, Robbins J (2005) Protein kinase C bound with A-kinase anchoring protein is involved in muscarinic receptor-activated modulation of M-type KCNQ potassium channels. Neurosci Res 51:231–234
Hille B, Dickson EJ, Kruse M, Vivas O, Suh BC (2015) Phosphoinositides regulate ion channels. Biochim Biophys Acta 1851:844–856
Holmes CL, Landry DW, Granton JT (2003) Science review: vasopressin and the cardiovascular system part 1--receptor physiology. Crit Care 7:427–434
Holt JR, Stauffer EA, Abraham D, Geleoc GS (2007) Dominant-negative inhibition of M-like potassium conductances in hair cells of the mouse inner ear. J Neurosci 27:8940–8951
Horikawa N, Suzuki T, Uchiumi T, Minamimura T, Tsukada K, Takeguchi N, Sakai H (2005) Cyclic AMP-dependent Cl- secretion induced by thromboxane A2 in isolated human colon. J Physiol 562:885–897
Hoshi N, Zhang JS, Omaki M, Takeuchi T, Yokoyama S, Wanaverbecq N, Langeberg LK, Yoneda Y, Scott JD, Brown DA, Higashida H (2003) AKAP150 signaling complex promotes suppression of the M-current by muscarinic agonists. Nat Neurosci 6:564–571
Hoshi N, Langeberg LK, Scott JD (2005) Distinct enzyme combinations in AKAP signalling complexes permit functional diversity. Nat Cell Biol
Hou P, Eldstrom J, Shi J, Zhong L, McFarland K, Gao Y, Fedida D, Cui J (2017) Inactivation of KCNQ1 potassium channels reveals dynamic coupling between voltage sensing and pore opening. Nat Commun 8:1730
Howard RJ, Clark KA, Holton JM, Minor DL Jr (2007) Structural insight into KCNQ (Kv7) channel assembly and channelopathy. Neuron 53:663–675
Huang H, Trussell LO (2011) KCNQ5 channels control resting properties and release probability of a synapse. Nat Neurosci 14:840–847
Hurley KM, Gaboyard S, Zhong M, Price SD, Wooltorton JR, Lysakowski A, Eatock RA (2006) M-like K+ currents in type I hair cells and calyx afferent endings of the developing rat utricle. J Neurosci 26:10253–10269
Iannotti FA, Panza E, Barrese V, Viggiano D, Soldovieri MV, Taglialatela M (2010) Expression, localization, and pharmacological role of Kv7 potassium channels in skeletal muscle proliferation, differentiation, and survival after myotoxic insults. J Pharmacol Exp Ther 332:811–820
Iannotti FA, Barrese V, Formisano L, Miceli F, Taglialatela M (2013) Specification of skeletal muscle differentiation by repressor element-1 silencing transcription factor (REST)-regulated Kv7.4 potassium channels. Mol Biol Cell 24:274–284
Inagaki A, Hayashi M, Andharia N, Matsuda H (2019) Involvement of butyrate in electrogenic K(+) secretion in rat rectal colon. Pflugers Arch 471:313–327
Ipavec V, Martire M, Barrese V, Taglialatela M, Currò D (2011) KV7 channels regulate muscle tone and nonadrenergic noncholinergic relaxation of the rat gastric fundus. Pharmacol Res 64:397–409
Jensen HS, Callo K, Jespersen T, Jensen BS, Olesen SP (2005) The KCNQ5 potassium channel from mouse: a broadly expressed M-current like potassium channel modulated by zinc, pH, and volume changes. Brain Res Mol Brain Res 139:52–62
Jepps TA, Greenwood IA, Moffatt JD, Sanders KM, Ohya S (2009) Molecular and functional characterization of Kv7 K+ channel in murine gastrointestinal smooth muscles. Am J Physiol Gastrointest Liver Physiol 297:G107–G115
Jepps TA, Chadha PS, Davis AJ, Harhun MI, Cockerill GW, Olesen SP, Hansen RS, Greenwood IA (2011) Downregulation of Kv7.4 channel activity in primary and secondary hypertension. Circulation 124:602–611
Jespersen T, Grunnet M, Olesen SP (2005) The KCNQ1 potassium channel: from gene to physiological function. Physiology (Bethesda) 20:408–416
Kaczmarek LK, Blumenthal EM (1997) Properties and regulation of the minK potassium channel protein. Physiol Rev 77:627–641
Kanaumi T, Takashima S, Iwasaki H, Itoh M, Mitsudome A, Hirose S (2008) Developmental changes in KCNQ2 and KCNQ3 expression in human brain: possible contribution to the age-dependent etiology of benign familial neonatal convulsions. Brain and Development 30:362–369
Kanda VA, Abbott GW (2012) KCNE regulation of K(+) channel trafficking – a Sisyphean task? Front Physiol 3:231
Kang C, Tian C, Sonnichsen FD, Smith JA, Meiler J, George AL Jr, Vanoye CG, Kim HJ, Sanders CR (2008) Structure of KCNE1 and implications for how it modulates the KCNQ1 potassium channel. Biochemistry 47:7999–8006
Kang S, Li J, Zuo W, Fu R, Gregor D, Krnjevic K, Bekker A, Ye JH (2017) Ethanol withdrawal drives anxiety-related behaviors by reducing M-type potassium channel activity in the lateral Habenula. Neuropsychopharmacology 42:1813–1824
Kapfhamer D, Berger KH, Hopf FW, Seif T, Kharazia V, Bonci A, Heberlein U (2010) Protein phosphatase 2a and glycogen synthase kinase 3 signaling modulate prepulse inhibition of the acoustic startle response by altering cortical M-type potassium channel activity. J Neurosci 30:8830–8840
Khanamiri S, Soltysinska E, Jepps TA, Bentzen BH, Chadha PS, Schmitt N, Greenwood IA, Olesen SP (2013) Contribution of Kv7 channels to basal coronary flow and active response to ischemia. Hypertension 62:1090–1097
Kharkovets T, Hardelin JP, Safieddine S, Schweizer M, El-Amraoui A, Petit C, Jentsch TJ (2000) KCNQ4, a K+ channel mutated in a form of dominant deafness, is expressed in the inner ear and the central auditory pathway. Proc Natl Acad Sci U S A 97:4333–4338
Kharkovets T, Dedek K, Maier H, Schweizer M, Khimich D, Nouvian R, Vardanyan V, Leuwer R, Moser T, Jentsch TJ (2006) Mice with altered KCNQ4 K+ channels implicate sensory outer hair cells in human progressive deafness. EMBO J 25:642–652
Kim HJ, Jeong MH, Kim KR, Jung CY, Lee SY, Kim H, Koh J, Vuong TA, Jung S, Yang H, Park SK, Choi D, Kim SH, Kang K, Sohn JW, Park JM, Jeon D, Koo SH, Ho WK, Kang JS, Kim ST, Cho H (2016) Protein arginine methylation facilitates KCNQ channel-PIP2 interaction leading to seizure suppression. eLife 5
Kim EC, Patel J, Zhang J, Soh H, Rhodes JS, Tzingounis AV, Chung HJ (2020) Heterozygous loss of epilepsy gene KCNQ2 alters social, repetitive and exploratory behaviors. Genes Brain Behav 19:e12599
Klinger F, Gould G, Boehm S, Shapiro MS (2011) Distribution of M-channel subunits KCNQ2 and KCNQ3 in rat hippocampus. NeuroImage 58:761–769
Korsgaard MP, Hartz BP, Brown WD, Ahring PK, Strøbaek D, Mirza NR (2005) Anxiolytic effects of Maxipost (BMS-204352) and retigabine via activation of neuronal Kv7 channels. J Pharmacol Exp Ther 314:282–292
Kosenko A, Hoshi N (2013) A change in configuration of the calmodulin-KCNQ channel complex underlies Ca2+−dependent modulation of KCNQ channel activity. PLoS One 8:e82290
Kosenko A, Moftakhar S, Wood MA, Hoshi N (2020) In vivo attenuation of M-current suppression impairs consolidation of object recognition memory. J Neurosci 40:5847–5856
Krishnan V, Han MH, Graham DL, Berton O, Renthal W, Russo SJ, Laplant Q, Graham A, Lutter M, Lagace DC, Ghose S, Reister R, Tannous P, Green TA, Neve RL, Chakravarty S, Kumar A, Eisch AJ, Self DW, Lee FS, Tamminga CA, Cooper DC, Gershenfeld HK, Nestler EJ (2007) Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 131:391–404
Krumerman A, Gao X, Bian JS, Melman YF, Kagan A, McDonald TV (2004) An LQT mutant minK alters KvLQT1 trafficking. Am J Physiol Cell Physiol 286:C1453–C1463
Kubisch C, Schroeder BC, Friedrich T, Lutjohann B, El-Amraoui A, Marlin S, Petit C, Jentsch TJ (1999) KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness. Cell 96:437–446
Kunzelmann K, Bleich M, Warth R, Levy-Holzman R, Garty H, Schreiber R (2001a) Expression and function of colonic epithelial KvLQT1 K+ channels. Clin Exp Pharmacol Physiol 28:79–83
Kunzelmann K, Hubner M, Schreiber R, Levy-Holzman R, Garty H, Bleich M, Warth R, Slavik M, von Hahn T, Greger R (2001b) Cloning and function of the rat colonic epithelial K+ channel KVLQT1. J Membr Biol 179:155–164
Kunzelmann K, Hübner M, Schreiber R, Levy-Holzman R, Garty H, Bleich M, Warth R, Slavik M, von Hahn T, Greger R (2001c) Cloning and function of the rat colonic epithelial K+ channel KVLQT1. J Membr Biol 179:155–164
Kurakami K, Norota I, Nasu F, Ohshima S, Nagasawa Y, Konno Y, Obara Y, Ishii K (2019) KCNQ1 is internalized by activation of alpha1 adrenergic receptors. Biochem Pharmacol 169:113628
Kurokawa J, Motoike HK, Rao J, Kass RS (2004) Regulatory actions of the A-kinase anchoring protein Yotiao on a heart potassium channel downstream of PKA phosphorylation. Proc Natl Acad Sci U S A 101:16374–16378
Lamas JA, Selyanko AA, Brown DA (1997) Effects of a cognition-enhancer, linopirdine (DuP 996), on M-type potassium currents (IK(M)) and some other voltage- and ligand-gated membrane currents in rat sympathetic neurons. Eur J Neurosci 9:605–616
Lambrecht NW, Yakubov I, Scott D, Sachs G (2005) Identification of the K efflux channel coupled to the gastric H-K-ATPase during acid secretion. Physiol Genomics 21:81–91
Langeberg LK, Scott JD (2005) A-kinase-anchoring proteins. J Cell Sci 118:3217–3220
Lee K, Isogai A, Antoh M, Kajioka S, Eto M, Hashitani H (2018) Role of K(+) channels in regulating spontaneous activity in the muscularis mucosae of Guinea pig bladder. Eur J Pharmacol 818:30–37
Lee JH, Chae MR, Kang SJ, Sung HH, Han DH, So I, Park JK, Lee SW (2020) Characterization and functional roles of KCNQ-encoded voltage-gated potassium (Kv7) channels in human corpus cavernosum smooth muscle. Pflugers Arch 472:89–102
Lehman A, Thouta S, Mancini GMS, Naidu S, van Slegtenhorst M, McWalter K, Person R, Mwenifumbo J, Salvarinova R, Guella I, McKenzie MB, Datta A, Connolly MB, Kalkhoran SM, Poburko D, Friedman JM, Farrer MJ, Demos M, Desai S, Claydon T (2017) Loss-of-function and gain-of-function mutations in KCNQ5 cause intellectual disability or epileptic encephalopathy. Am J Hum Genet 101:65–74
Leitner MG, Feuer A, Ebers O, Schreiber DN, Halaszovich CR, Oliver D (2012) Restoration of ion channel function in deafness-causing KCNQ4 mutants by synthetic channel openers. Br J Pharmacol 165:2244–2259
Lerche C, Scherer CR, Seebohm G, Derst C, Wei AD, Busch AE, Steinmeyer K (2000) Molecular cloning and functional expression of KCNQ5, a potassium channel subunit that may contribute to neuronal M-current diversity. J Biol Chem 275:22395–22400
Li Y, Gamper N, Shapiro MS (2004a) Single-channel analysis of KCNQ K+ channels reveals the mechanism of augmentation by a cysteine-modifying reagent. J Neurosci 24:5079–5090
Li Y, Langlais P, Gamper N, Liu F, Shapiro MS (2004b) Dual phosphorylations underlie modulation of unitary KCNQ K(+) channels by Src tyrosine kinase. J Biol Chem 279:45399–45407
Li Y, Gamper N, Hilgemann DW, Shapiro MS (2005) Regulation of Kv7 (KCNQ) K+ channel open probability by phosphatidylinositol (4,5)-bisphosphate. J Neurosci 25:9825–9835
Li C, Huang P, Lu Q, Zhou M, Guo L, Xu X (2014) KCNQ/Kv7 channel activator flupirtine protects against acute stress-induced impairments of spatial memory retrieval and hippocampal LTP in rats. Neuroscience 280:19–30
Li L, Sun H, Ding J, Niu C, Su M, Zhang L, Li Y, Wang C, Gamper N, Du X, Zhang H (2017) Selective targeting of M-type potassium Kv 7.4 channels demonstrates their key role in the regulation of dopaminergic neuronal excitability and depression-like behaviour. Br J Pharmacol 174:4277–4294
Li J, Maghera J, Lamothe SM, Marco EJ, Kurata HT (2020) Heteromeric assembly of truncated neuronal Kv7 channels: implications for neurologic disease and pharmacotherapy. Mol Pharmacol 98:192–202
Li X, Zhang Q, Guo P, Fu J, Mei L, Lv D, Wang J, Lai D, Ye S, Yang H, Guo J (2021) Molecular basis for ligand activation of the human KCNQ2 channel. Cell Res 31:52–61
Liao X, Yap MKH, Leung KH, Kao PYP, Liu LQ, Yip SP (2017) Genetic association study of KCNQ5 polymorphisms with high myopia. Biomed Res Int 2017:3024156
Linley JE, Rose K, Patil M, Robertson B, Akopian AN, Gamper N (2008) Inhibition of M current in sensory neurons by exogenous proteases: a signaling pathway mediating inflammatory nociception. J Neurosci 28:11240–11249
Liu W, Devaux JJ (2014) Calmodulin orchestrates the heteromeric assembly and the trafficking of KCNQ2/3 (Kv7.2/3) channels in neurons. Mol Cell Neurosci 58:40–52
Liu B, Linley JE, Du X, Zhang X, Ooi L, Zhang H, Gamper N (2010) The acute nociceptive signals induced by bradykinin in rat sensory neurons are mediated by inhibition of M-type K+ channels and activation of Ca2+−activated Cl- channels. J Clin Invest 120:1240–1252
Liu H, Jia L, Chen X, Shi L, Xie J (2018) The Kv7/KCNQ channel blocker XE991 protects nigral dopaminergic neurons in the 6-hydroxydopamine rat model of Parkinson’s disease. Brain Res Bull 137:132–139
Lohrmann E, Burhoff I, Nitschke RB, Lang HJ, Mania D, Englert HC, Hropot M, Warth R, Rohm W, Bleich M et al (1995) A new class of inhibitors of cAMP-mediated Cl- secretion in rabbit colon, acting by the reduction of cAMP-activated K+ conductance. Pflugers Arch 429:517–530
Loussouarn G, Park KH, Bellocq C, Baro II, Charpentier F, Escande D (2003) Phosphatidylinositol-4,5-bisphosphate, PIP(2), controls KCNQ1/KCNE1 voltage-gated potassium channels: a functional homology between voltage-gated and inward rectifier K(+) channels. EMBO J 22:5412–5421
Loussouarn G, Baro I, Escande D (2006) KCNQ1 K+ channel-mediated cardiac channelopathies. Methods Mol Biol 337:167–183
Lubke M, Schreiber JA, Le Quoc T, Korber F, Muller J, Sivanathan S, Matschke V, Schubert J, Strutz-Seebohm N, Seebohm G, Scherkenbeck J (2020) Rottlerin: structure modifications and KCNQ1/KCNE1 ion channel activity. ChemMedChem 15:1078–1088
Lv P, Wei D, Yamoah EN (2010) Kv7-type channel currents in spiral ganglion neurons: involvement in sensorineural hearing loss. J Biol Chem 285:34699–34707
Mackie AR, Brueggemann LI, Henderson KK, Shiels AJ, Cribbs LL, Scrogin KE, Byron KL (2008) Vascular KCNQ potassium channels as novel targets for the control of mesenteric artery constriction by vasopressin, based on studies in single cells, pressurized arteries, and in vivo measurements of mesenteric vascular resistance. J Pharmacol Exp Ther 325:475–483
Maljevic S, Lerche C, Seebohm G, Alekov AK, Busch AE, Lerche H (2003) C-terminal interaction of KCNQ2 and KCNQ3 K+ channels. J Physiol 548:353–360
Mall M, Wissner A, Schreiber R, Kuehr J, Seydewitz HH, Brandis M, Greger R, Kunzelmann K (2000) Role of K(V)LQT1 in cyclic adenosine monophosphate-mediated Cl(-) secretion in human airway epithelia. Am J Respir Cell Mol Biol 23:283–289
Mani BK, Brueggemann LI, Cribbs LL, Byron KL (2011) Activation of vascular KCNQ (Kv7) potassium channels reverses spasmogen-induced constrictor responses in rat basilar artery. Br J Pharmacol 164:237–249
Mani BK, O’Dowd J, Kumar L, Brueggemann LI, Ross M, Byron KL (2013) Vascular KCNQ (Kv7) potassium channels as common signaling intermediates and therapeutic targets in cerebral vasospasm. J Cardiovasc Pharmacol 61:51–62
Mani BK, Robakowski C, Brueggemann LI, Cribbs LL, Tripathi A, Majetschak M, Byron KL (2016) Kv7.5 potassium channel subunits are the primary targets for PKA-dependent enhancement of vascular smooth muscle Kv7 currents. Mol Pharmacol 89:323–334
Marcotti W, Kros CJ (1999) Developmental expression of the potassium current IK,n contributes to maturation of mouse outer hair cells. J Physiol 520(Pt 3):653–660
Marx S (2003) Ion channel macromolecular complexes in the heart. J Mol Cell Cardiol 35:37–44
Marx SO, Kurokawa J, Reiken S, Motoike H, D’Armiento J, Marks AR, Kass RS (2002) Requirement of a macromolecular signaling complex for beta adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel. Science 295:496–499
Mayordomo-Cava J, Yajeya J, Navarro-López JD, Jiménez-Díaz L (2015) Amyloid-β(25-35) modulates the expression of GirK and KCNQ Channel genes in the Hippocampus. PLoS One 10:e0134385
McCallum LA, Greenwood IA, Tribe RM (2009) Expression and function of K(v)7 channels in murine myometrium throughout oestrous cycle. Pflugers Arch 457:1111–1120
McCrossan ZA, Abbott GW (2004) The MinK-related peptides. Neuropharmacology 47:787–821
McGuier NS, Griffin WC 3rd, Gass JT, Padula AE, Chesler EJ, Mulholland PJ (2016) Kv7 channels in the nucleus accumbens are altered by chronic drinking and are targets for reducing alcohol consumption. Addict Biol 21:1097–1112
Mehregan H, Mohseni M, Akbari M, Jalalvand K, Arzhangi S, Nikzat N, Kahrizi K, Najmabadi H (2019) Novel mutations in KCNQ4, LHFPL5 and COCH genes in Iranian families with hearing impairment. Arch Iran Med 22:189–197
Meisel E, Tobelaim W, Dvir M, Haitin Y, Peretz A, Attali B (2018) Inactivation gating of Kv7.1 channels does not involve concerted cooperative subunit interactions. Channels (Austin) 12:89–99
Mena A, Ruiz-Salas JC, Puentes A, Dorado I, Ruiz-Veguilla M, De la Casa LG (2016) Reduced prepulse inhibition as a biomarker of schizophrenia. Front Behav Neurosci 10:202
Mencia A, Gonzalez-Nieto D, Modamio-Hoybjor S, Etxeberria A, Aranguez G, Salvador N, Del Castillo I, Villarroel A, Moreno F, Barrio L, Moreno-Pelayo MA (2008) A novel KCNQ4 pore-region mutation (p.G296S) causes deafness by impairing cell-surface channel expression. Hum Genet 123:41–53
Metten P, Iancu OD, Spence SE, Walter NA, Oberbeck D, Harrington CA, Colville A, McWeeney S, Phillips TJ, Buck KJ, Crabbe JC, Belknap JK, Hitzemann RJ (2014) Dual-trait selection for ethanol consumption and withdrawal: genetic and transcriptional network effects. Alcohol Clin Exp Res 38:2915–2924
Miceli F, Soldovieri MV, Ambrosino P, De Maria M, Migliore M, Migliore R, Taglialatela M (2015) Early-onset epileptic encephalopathy caused by gain-of-function mutations in the voltage sensor of Kv7.2 and Kv7.3 potassium channel subunits. J Neurosci 35:3782–3793
Mondejar-Parreno G, Perez-Vizcaino F, Cogolludo A (2020) Kv7 channels in lung diseases. Front Physiol 11:634
Moore SD, Madamba SG, Siggins GR (1990) Ethanol diminishes a voltage-dependent K+ current, the M-current, in CA1 hippocampal pyramidal neurons in vitro. Brain Res 516:222–228
Moreno C, Oliveras A, de la Cruz A, Bartolucci C, Munoz C, Salar E, Gimeno JR, Severi S, Comes N, Felipe A, Gonzalez T, Lambiase P, Valenzuela C (2015) A new KCNQ1 mutation at the S5 segment that impairs its association with KCNE1 is responsible for short QT syndrome. Cardiovasc Res 107:613–623
Moreno C, Oliveras A, Bartolucci C, Munoz C, de la Cruz A, Peraza DA, Gimeno JR, Martin-Martinez M, Severi S, Felipe A, Lambiase PD, Gonzalez T, Valenzuela C (2017) D242N, a KV7.1 LQTS mutation uncovers a key residue for IKs voltage dependence. J Mol Cell Cardiol 110:61–69
Mucha M, Ooi L, Linley JE, Mordaka P, Dalle C, Robertson B, Gamper N, Wood IC (2010) Transcriptional control of KCNQ channel genes and the regulation of neuronal excitability. J Neurosci 30:13235–13245
Munro G, Erichsen HK, Mirza NR (2007) Pharmacological comparison of anticonvulsant drugs in animal models of persistent pain and anxiety. Neuropharmacology 53:609–618
Murray CI, Westhoff M, Eldstrom J, Thompson E, Emes R, Fedida D (2016) Unnatural amino acid photo-crosslinking of the IKs channel complex demonstrates a KCNE1:KCNQ1 stoichiometry of up to 4:4. eLife 5
Nakajo K, Kubo Y (2007) KCNE1 and KCNE3 stabilize and/or slow voltage sensing S4 segment of KCNQ1 channel. J Gen Physiol 130:269–281
Nakajo K, Kubo Y (2014) Steric hindrance between S4 and S5 of the KCNQ1/KCNE1 channel hampers pore opening. Nat Commun 5:4100
Nakajo K, Ulbrich MH, Kubo Y, Isacoff EY (2010) Stoichiometry of the KCNQ1 – KCNE1 ion channel complex. Proc Natl Acad Sci U S A 107:18862–18867
Neyroud N, Tesson F, Denjoy I, Leibovici M, Donger C, Barhanin J, Faure S, Gary F, Coumel P, Petit C, Schwartz K, Guicheney P (1997) A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome. Nat Genet 15:186–189
Ng FL, Davis AJ, Jepps TA, Harhun MI, Yeung SY, Wan A, Reddy M, Melville D, Nardi A, Khong TK, Greenwood IA (2011) Expression and function of the K+ channel KCNQ genes in human arteries. Br J Pharmacol 162:42–53
Nicolas M, Dememes D, Martin A, Kupershmidt S, Barhanin J (2001) KCNQ1/KCNE1 potassium channels in mammalian vestibular dark cells. Hear Res 153:132–145
Nicolas CS, Park KH, El Harchi A, Camonis J, Kass RS, Escande D, Merot J, Loussouarn G, Le Bouffant F, Baro I (2008) IKs response to protein kinase A-dependent KCNQ1 phosphorylation requires direct interaction with microtubules. Cardiovasc Res 79:427–435
Nouvian R, Ruel J, Wang J, Guitton MJ, Pujol R, Puel JL (2003) Degeneration of sensory outer hair cells following pharmacological blockade of cochlear KCNQ channels in the adult Guinea pig. Eur J Neurosci 17:2553–2562
Nunez E, Muguruza-Montero A, Villarroel A (2020) Atomistic insights of calmodulin gating of complete ion channels. Int J Mol Sci 21
Ohya S, Asakura K, Muraki K, Watanabe M, Imaizumi Y (2002) Molecular and functional characterization of ERG, KCNQ, and KCNE subtypes in rat stomach smooth muscle. Am J Physiol Gastrointest Liver Physiol 282:G277–G287
Ohya S, Sergeant GP, Greenwood IA, Horowitz B (2003) Molecular variants of KCNQ channels expressed in murine portal vein myocytes: a role in delayed rectifier current. Circ Res 92:1016–1023
Oliver D, Knipper M, Derst C, Fakler B (2003) Resting potential and submembrane calcium concentration of inner hair cells in the isolated mouse cochlea are set by KCNQ-type potassium channels. J Neurosci 23:2141–2149
Osteen JD, Gonzalez C, Sampson KJ, Iyer V, Rebolledo S, Larsson HP, Kass RS (2010) KCNE1 alters the voltage sensor movements necessary to open the KCNQ1 channel gate. Proc Natl Acad Sci U S A 107:22710–22715
Osteen JD, Barro-Soria R, Robey S, Sampson KJ, Kass RS, Larsson HP (2012) Allosteric gating mechanism underlies the flexible gating of KCNQ1 potassium channels. Proc Natl Acad Sci U S A 109:7103–7108
Owen DG, Marsh SJ, Brown DA (1990) M-current noise and putative M-channels in cultured rat sympathetic ganglion cells. J Physiol Lond 431:269–290
Pan Z, Kao T, Horvath Z, Lemos J, Sul JY, Cranstoun SD, Bennett V, Scherer SS, Cooper EC (2006) A common ankyrin-G-based mechanism retains KCNQ and NaV channels at electrically active domains of the axon. J Neurosci 26:2599–2613
Park KH, Piron J, Dahimene S, Merot J, Baro I, Escande D, Loussouarn G (2005) Impaired KCNQ1-KCNE1 and phosphatidylinositol-4,5-bisphosphate interaction underlies the long QT syndrome. Circ Res 96:730–739
Parrilla-Carrero J, Buchta WC, Goswamee P, Culver O, McKendrick G, Harlan B, Moutal A, Penrod R, Lauer A, Ramakrishnan V, Khanna R, Kalivas P, Riegel AC (2018) Restoration of Kv7 channel-mediated inhibition reduces cued-reinstatement of cocaine seeking. J Neurosci 38:4212–4229
Passmore GM, Selyanko AA, Mistry M, Al-Qatari M, Marsh SJ, Matthews EA, Dickenson AH, Brown TA, Burbidge SA, Main M, Brown DA (2003) KCNQ/M currents in sensory neurons: significance for pain therapy. J Neurosci 23:7227–7236
Peng H, Bian XL, Ma FC, Wang KW (2017) Pharmacological modulation of the voltage-gated neuronal Kv7/KCNQ/M-channel alters the intrinsic excitability and synaptic responses of pyramidal neurons in rat prefrontal cortex slices. Acta Pharmacol Sin 38:1248–1256
Perez-Flores MC, Lee JH, Park S, Zhang XD, Sihn CR, Ledford HA, Wang W, Kim HJ, Timofeyev V, Yarov-Yarovoy V, Chiamvimonvat N, Rabbitt RD, Yamoah EN (2020) Cooperativity of Kv7.4 channels confers ultrafast electromechanical sensitivity and emergent properties in cochlear outer hair cells. Sci Adv 6:eaba1104
Peroz D, Dahimene S, Baro I, Loussouarn G, Merot J (2009) LQT1-associated mutations increase KCNQ1 proteasomal degradation independently of Derlin-1. J Biol Chem 284:5250–5256
Peters HC, Hu H, Pongs O, Storm JF, Isbrandt D (2005) Conditional transgenic suppression of M channels in mouse brain reveals functions in neuronal excitability, resonance and behavior. Nat Neurosci 8:51–60
Pobbe RL, Zangrossi H Jr (2008) Involvement of the lateral habenula in the regulation of generalized anxiety- and panic-related defensive responses in rats. Life Sci 82:1256–1261
Pongs O, Schwarz JR (2010) Ancillary subunits associated with voltage-dependent K+ channels. Physiol Rev 90:755–796
Provence A, Malysz J, Petkov GV (2015) The novel KV7.2/KV7.3 channel opener ICA-069673 reveals subtype-specific functional roles in Guinea pig detrusor smooth muscle excitability and contractility. J Pharmacol Exp Ther 354:290–301
Provence A, Angoli D, Petkov GV (2018) K(V)7 channel pharmacological activation by the novel activator ML213: role for Heteromeric K(V)7.4/K(V)7.5 channels in Guinea pig detrusor smooth muscle function. J Pharmacol Exp Ther 364:131–144
Pusch M (1998) Increase of the single-channel conductance of KvLQT1 potassium channels induced by the association with minK. Pflugers Arch 437:172–174
Redrobe JP, Nielsen AN (2009) Effects of neuronal Kv7 potassium channel activators on hyperactivity in a rodent model of mania. Behav Brain Res 198:481–485
Regev N, Degani-Katzav N, Korngreen A, Etzioni A, Siloni S, Alaimo A, Chikvashvili D, Villarroel A, Attali B, Lotan I (2009) Selective interaction of syntaxin 1A with KCNQ2: possible implications for specific modulation of presynaptic activity. PLoS One 4:e6586
Reilly JM, Passmore GM, Marsh SJ, Brown DA (2013) Kv7/M-type potassium channels in rat skin keratinocytes. Pflugers Arch 465:1371–1381
Restier L, Cheng L, Sanguinetti MC (2008) Mechanisms by which atrial fibrillation-associated mutations in the S1 domain of KCNQ1 slow deactivation of IKs channels. J Physiol 586:4179–4191
Rinker JA, Mulholland PJ (2017) Promising pharmacogenetic targets for treating alcohol use disorder: evidence from preclinical models. Pharmacogenomics 18:555–570
Rinker JA, Fulmer DB, Trantham-Davidson H, Smith ML, Williams RW, Lopez MF, Randall PK, Chandler LJ, Miles MF, Becker HC, Mulholland PJ (2017) Differential potassium channel gene regulation in BXD mice reveals novel targets for pharmacogenetic therapies to reduce heavy alcohol drinking. Alcohol (Fayetteville, NY) 58:33–45
Rocheleau JM, Kobertz WR (2008) KCNE peptides differently affect voltage sensor equilibrium and equilibration rates in KCNQ1 K+ channels. J Gen Physiol 131:59–68
Roepke TK, Anantharam A, Kirchhoff P, Busque SM, Young JB, Geibel JP, Lerner DJ, Abbott GW (2006) The KCNE2 potassium channel ancillary subunit is essential for gastric acid secretion. J Biol Chem 281:23740–23747
Romey G, Attali B, Chouabe C, Abitbol I, Guillemare E, Barhanin J, Lazdunski M (1997) Molecular mechanism and functional significance of the MinK control of the KvLQT1 channel activity. J Biol Chem 272:16713–16716
Rose K, Ooi L, Dalle C, Robertson B, Wood IC, Gamper N (2011) Transcriptional repression of the M channel subunit Kv7.2 in chronic nerve injury. Pain 152:742–754
Roura-Ferrer M, Sole L, Martinez-Marmol R, Villalonga N, Felipe A (2008) Skeletal muscle Kv7 (KCNQ) channels in myoblast differentiation and proliferation. Biochem Biophys Res Commun 369:1094–1097
Ruscic KJ, Miceli F, Villalba-Galea CA, Dai H, Mishina Y, Bezanilla F, Goldstein SA (2013) IKs channels open slowly because KCNE1 accessory subunits slow the movement of S4 voltage sensors in KCNQ1 pore-forming subunits. Proc Natl Acad Sci U S A 110:E559–E566
Ryan A, Dallos P (1975) Effect of absence of cochlear outer hair cells on behavioural auditory threshold. Nature 253:44–46
Sachyani D, Dvir M, Strulovich R, Tria G, Tobelaim W, Peretz A, Pongs O, Svergun D, Attali B, Hirsch JA (2014) Structural basis of a Kv7.1 potassium channel gating module: studies of the intracellular c-terminal domain in complex with calmodulin. Structure 22:1582–1594
Sanguinetti MC, Curran ME, Zou A, Shen J, Spector PS, Atkinson DL, Keating MT (1996) Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel. Nature 384:80–83
Sankaranarayanan S, Simasko SM (1996) Characterization of an M-like current modulated by thyrotropin-releasing hormone in normal rat lactotrophs. J Neurosci 16:1668–1678
Schenzer A, Friedrich T, Pusch M, Saftig P, Jentsch TJ, Grotzinger J, Schwake M (2005) Molecular determinants of KCNQ (Kv7) K+ channel sensitivity to the anticonvulsant retigabine. J Neurosci 25:5051–5060
Schmitt N, Schwarz M, Peretz A, Abitbol I, Attali B, Pongs O (2000) A recessive C-terminal Jervell and Lange-Nielsen mutation of the KCNQ1 channel impairs subunit assembly. EMBO J 19:332–340
Schroeder BC, Hechenberger M, Weinreich F, Kubisch C, Jentsch TJ (2000a) KCNQ5, a novel potassium channel broadly expressed in brain, mediates M-type currents. J Biol Chem 275:24089–24095
Schroeder BC, Waldegger S, Fehr S, Bleich M, Warth R, Greger R, Jentsch TJ (2000b) A constitutively open potassium channel formed by KCNQ1 and KCNE3. Nature 403:196–199
Schulze-Bahr E, Wang Q, Wedekind H, Haverkamp W, Chen Q, Sun Y, Rubie C, Hordt M, Towbin JA, Borggrefe M, Assmann G, Qu X, Somberg JC, Breithardt G, Oberti C, Funke H (1997) KCNE1 mutations cause jervell and Lange-Nielsen syndrome. Nat Genet 17:267–268
Schwab SG, Knapp M, Sklar P, Eckstein GN, Sewekow C, Borrmann-Hassenbach M, Albus M, Becker T, Hallmayer JF, Lerer B, Maier W, Wildenauer DB (2006) Evidence for association of DNA sequence variants in the phosphatidylinositol-4-phosphate 5-kinase IIalpha gene (PIP5K2A) with schizophrenia. Mol Psychiatry 11:837–846
Schwake M, Jentsch TJ, Friedrich T (2003) A carboxy-terminal domain determines the subunit specificity of KCNQ K(+) channel assembly. EMBO Rep 4:76–81
Schwake M, Athanasiadu D, Beimgraben C, Blanz J, Beck C, Jentsch TJ, Saftig P, Friedrich T (2006) Structural determinants of M-type KCNQ (Kv7) K+ channel assembly. J Neurosci 26:3757–3766
Seebohm G, Scherer CR, Busch AE, Lerche C (2001) Identification of specific pore residues mediating KCNQ1 inactivation. A novel mechanism for long QT syndrome. J Biol Chem 276:13600–13605
Seebohm G, Strutz-Seebohm N, Birkin R, Dell G, Bucci C, Spinosa MR, Baltaev R, Mack AF, Korniychuk G, Choudhury A, Marks D, Pagano RE, Attali B, Pfeufer A, Kass RS, Sanguinetti MC, Tavare JM, Lang F (2007) Regulation of endocytic recycling of KCNQ1/KCNE1 potassium channels. Circ Res 100:686–692
Seebohm G, Strutz-Seebohm N, Ureche ON, Henrion U, Baltaev R, Mack AF, Korniychuk G, Steinke K, Tapken D, Pfeufer A, Kaab S, Bucci C, Attali B, Merot J, Tavare JM, Hoppe UC, Sanguinetti MC, Lang F (2008) Long QT syndrome-associated mutations in KCNQ1 and KCNE1 subunits disrupt normal endosomal recycling of IKs channels. Circ Res 103:1451–1457
Seefeld MA, Lin H, Holenz J, Downie D, Donovan B, Fu T, Pasikanti K, Zhen W, Cato M, Chaudhary KW, Brady P, Bakshi T, Morrow D, Rajagopal S, Samanta SK, Madhyastha N, Kuppusamy BM, Dougherty RW, Bhamidipati R, Mohd Z, Higgins GA, Chapman M, Rouget C, Lluel P, Matsuoka Y (2018) Novel K(V)7 ion channel openers for the treatment of epilepsy and implications for detrusor tissue contraction. Bioorg Med Chem Lett 28:3793–3797
Selyanko AA, Brown DA (1996) Intracellular calcium directly inhibits potassium M channels in excised membrane patches from rat sympathetic neurons. Neuron 16:151–162
Selyanko AA, Brown DA (1999) M-channel gating and simulation. Biophys J 77:701–713
Selyanko AA, Hadley JK, Wood IC, Abogadie FC, Jentsch TJ, Brown DA (2000) Inhibition of KCNQ1-4 potassium channels expressed in mammalian cells via M1 muscarinic acetylcholine receptors. J Physiol (Lond) 522(Pt 3):349–355
Selyanko AA, Hadley JK, Brown DA (2001) Properties of single M-type KCNQ2/KCNQ3 potassium channels expressed in mammalian cells. J Physiol 534:15–24
Sesti F, Goldstein SA (1998) Single-channel characteristics of wild-type IKs channels and channels formed with two minK mutants that cause long QT syndrome. J Gen Physiol 112:651–663
Shah A, Zuo W, Kang S, Li J, Fu R, Zhang H, Bekker A, Ye JH (2017) The lateral habenula and alcohol: role of glutamate and M-type potassium channels. Pharmacol Biochem Behav 162:94–102
Shalaby FY, Levesque PC, Yang WP, Little WA, Conder ML, Jenkins-West T, Blanar MA (1997) Dominant-negative KvLQT1 mutations underlie the LQT1 form of long QT syndrome. Circulation 96:1733–1736
Shamgar L, Ma L, Schmitt N, Haitin Y, Peretz A, Wiener R, Hirsch J, Pongs O, Attali B (2006) Calmodulin is essential for cardiac IKS channel gating and assembly. Impaired function in long-QT mutations. Circ Res 98:1055–1063
Shapiro MS, Wollmuth LP, Hille B (1994) Angiotensin II inhibits calcium and M current channels in rat sympathetic neurons via G proteins. Neuron 12:1319–1329
Shapiro MS, Roche JP, Kaftan EJ, Cruzblanca H, Mackie K, Hille B (2000) Reconstitution of muscarinic modulation of the KCNQ2/KCNQ3 K(+) channels that underlie the neuronal M current. J Neurosci 20:1710–1721
Sihn CR, Kim HJ, Woltz RL, Yarov-Yarovoy V, Yang PC, Xu J, Clancy CE, Zhang XD, Chiamvimonvat N, Yamoah EN (2016) Mechanisms of calmodulin regulation of different isoforms of Kv7.4 K+ channels. J Biol Chem 291:2499–2509
Singh NA, Charlier C, Stauffer D, DuPont BR, Leach RJ, Melis R, Ronen GM, Bjerre I, Quattlebaum T, Murphy JV, McHarg ML, Gagnon D, Rosales TO, Peiffer A, Anderson VE, Leppert M (1998) A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat Genet 18:25–29
Slomko AM, Naseer Z, Ali SS, Wongvravit JP, Friedman LK (2014) Retigabine calms seizure-induced behavior following status epilepticus. Epilepsy Behav E&B 37:123–132
Sogaard R, Ljungstrom T, Pedersen KA, Olesen SP, Jensen BS (2001) KCNQ4 channels expressed in mammalian cells: functional characteristics and pharmacology. Am J Physiol Cell Physiol 280:C859–C866
Soldovieri MV, Miceli F, Taglialatela M (2011) Driving with no brakes: molecular pathophysiology of Kv7 potassium channels. Physiology (Bethesda) 26:365–376
Sousa AD, Andrade LR, Salles FT, Pillai AM, Buttermore ED, Bhat MA, Kachar B (2009) The septate junction protein caspr is required for structural support and retention of KCNQ4 at calyceal synapses of vestibular hair cells. J Neurosci 29:3103–3108
Spitzmaul G, Tolosa L, Winkelman BH, Heidenreich M, Frens MA, Chabbert C, de Zeeuw CI, Jentsch TJ (2013) Vestibular role of KCNQ4 and KCNQ5 K+ channels revealed by mouse models. J Biol Chem 288:9334–9344
Stansfeld CE, Marsh SJ, Gibb AJ, Brown DA (1993) Identification of M-channels in outside-out patches excised from sympathetic ganglion cells. Neuron 10:639–654
Stott JB, Jepps TA, Greenwood IA (2014) K(V)7 potassium channels: a new therapeutic target in smooth muscle disorders. Drug Discov Today 19:413–424
Stott JB, Barrese V, Jepps TA, Leighton EV, Greenwood IA (2015) Contribution of Kv7 channels to natriuretic peptide mediated vasodilation in normal and hypertensive rats. Hypertension 65:676–682
Strutz-Seebohm N, Seebohm G, Fedorenko O, Baltaev R, Engel J, Knirsch M, Lang F (2006) Functional coassembly of KCNQ4 with KCNE-beta- subunits in Xenopus oocytes. Cell Physiol Biochem 18:57–66
Strutz-Seebohm N, Pusch M, Wolf S, Stoll R, Tapken D, Gerwert K, Attali B, Seebohm G (2011) Structural basis of slow activation gating in the cardiac I Ks channel complex. Cell Physiol Biochem 27:443–452
Su CC, Yang JJ, Shieh JC, Su MC, Li SY (2007) Identification of novel mutations in the KCNQ4 gene of patients with nonsyndromic deafness from Taiwan. Audiol Neurootol 12:20–26
Su TR, Zei WS, Su CC, Hsiao G, Lin MJ (2012) The effects of the KCNQ openers retigabine and flupirtine on myotonia in mammalian skeletal muscle induced by a chloride channel blocker. Evid Based Complement Alternat Med 2012:803082
Su M, Li L, Wang J, Sun H, Zhang L, Zhao C, Xie Y, Gamper N, Du X, Zhang H (2019) Kv7.4 channel contribute to projection-specific auto-inhibition of dopamine neurons in the ventral tegmental area. Front Cell Neurosci 13:557
Suessbrich H, Bleich M, Ecke D, Rizzo M, Waldegger S, Lang F, Szabo I, Lang HJ, Kunzelmann K, Greger R, Busch AE (1996) Specific blockade of slowly activating I(sK) channels by chromanols -- impact on the role of I(sK) channels in epithelia. FEBS Lett 396:271–275
Suh B, Hille B (2002) Recovery from muscarinic modulation of M current channels requires phosphatidylinositol 4,5-bisphosphate synthesis. Neuron 35:507–520
Sun J, MacKinnon R (2017) Cryo-EM structure of a KCNQ1/CaM complex reveals insights into congenital long QT syndrome. Cell 169:1042–1050.e9
Sun J, MacKinnon R (2020) Structural basis of human KCNQ1 modulation and gating. Cell 180:340–347.e9
Sun H, Lin AH, Ru F, Patil MJ, Meeker S, Lee LY, Undem BJ (2019) KCNQ/M-channels regulate mouse vagal bronchopulmonary C-fiber excitability and cough sensitivity. JCI Insight 4
Svalø J, Bille M, Parameswaran Theepakaran N, Sheykhzade M, Nordling J, Bouchelouche P (2013) Bladder contractility is modulated by Kv7 channels in pig detrusor. Eur J Pharmacol 715:312–320
Svalø J, Sheykhzade M, Nordling J, Matras C, Bouchelouche P (2015) Functional and molecular evidence for Kv7 channel subtypes in human detrusor from patients with and without bladder outflow obstruction. PLoS One 10:e0117350
Takahira M, Hughes BA (1997) Isolated bovine retinal pigment epithelial cells express delayed rectifier type and M-type K+ currents. Am J Phys 273:C790–C803
Talebizadeh Z, Kelley PM, Askew JW, Beisel KW, Smith SD (1999) Novel mutation in the KCNQ4 gene in a large kindred with dominant progressive hearing loss. Hum Mutat 14:493–501
Tatulian L, Brown DA (2003) Effect of the KCNQ potassium channel opener retigabine on single KCNQ2/3 channels expressed in CHO cells. J Physiol 549:57–63
Tatulian L, Delmas P, Abogadie FC, Brown DA (2001) Activation of expressed KCNQ potassium currents and native neuronal M- type potassium currents by the anti-convulsant drug retigabine. J Neurosci 21:5535–5545
Telezhkin V, Brown DA, Gibb AJ (2012) Distinct subunit contributions to the activation of M-type potassium channels by PI(4,5)P2. J Gen Physiol 140:41–53
Tian C, Vanoye CG, Kang C, Welch RC, Kim HJ, George AL Jr, Sanders CR (2007) Preparation, functional characterization, and NMR studies of human KCNE1, a voltage-gated potassium channel accessory subunit associated with deafness and long QT syndrome. Biochemistry 46:11459–11472
Tinel N, Diochot S, Borsotto M, Lazdunski M, Barhanin J (2000a) KCNE2 confers background current characteristics to the cardiac KCNQ1 potassium channel. EMBO J 19:6326–6330
Tinel N, Diochot S, Lauritzen I, Barhanin J, Lazdunski M, Borsotto M (2000b) M-type KCNQ2-KCNQ3 potassium channels are modulated by the KCNE2 subunit. FEBS Lett 480:137–141
Tobelaim WS, Dvir M, Lebel G, Cui M, Buki T, Peretz A, Marom M, Haitin Y, Logothetis DE, Hirsch JA, Attali B (2017) Competition of calcified calmodulin N lobe and PIP2 to an LQT mutation site in Kv7.1 channel. Proc Natl Acad Sci U S A 114:E869–E878
Tristani-Firouzi M, Sanguinetti MC (1998) Voltage-dependent inactivation of the human K+ channel KvLQT1 is eliminated by association with minimal K+ channel (minK) subunits. J Physiol Lond 510:37–45
Tsai YM, Jones F, Mullen P, Porter KE, Steely D, Peers C, Gamper N (2020) Vascular Kv7 channels control intracellular Ca2+ dynamics in smooth muscle. Cell Calcium 92:102283
Tunquist BJ, Hoshi N, Guire ES, Zhang F, Mullendorff K, Langeberg LK, Raber J, Scott JD (2008) Loss of AKAP150 perturbs distinct neuronal processes in mice. Proc Natl Acad Sci U S A 105:12557–12562
Tykocki NR, Heppner TJ, Dalsgaard T, Bonev AD, Nelson MT (2019) The K(V) 7 channel activator retigabine suppresses mouse urinary bladder afferent nerve activity without affecting detrusor smooth muscle K(+) channel currents. J Physiol 597:935–950
Tzingounis AV, Heidenreich M, Kharkovets T, Spitzmaul G, Jensen HS, Nicoll RA, Jentsch TJ (2010) The KCNQ5 potassium channel mediates a component of the afterhyperpolarization current in mouse hippocampus. Proc Natl Acad Sci U S A 107:10232–10237
Uchida H, Ma L, Ueda H (2010) Epigenetic gene silencing underlies C-fiber dysfunctions in neuropathic pain. J Neurosci 30:4806–4814
Vallon V, Grahammer F, Richter K, Bleich M, Lang F, Barhanin J, Volkl H, Warth R (2001) Role of KCNE1-dependent K+ fluxes in mouse proximal tubule. J Am Soc Nephrol 12:2003–2011
Van Camp G, Coucke PJ, Akita J, Fransen E, Abe S, De Leenheer EM, Huygen PL, Cremers CW, Usami S (2002) A mutational hot spot in the KCNQ4 gene responsible for autosomal dominant hearing impairment. Hum Mutat 20:15–19
van der Horst J, Greenwood IA, Jepps TA (2020) Cyclic AMP-dependent regulation of Kv7 voltage-gated potassium channels. Front Physiol 11:727
Van Hauwe P, Coucke PJ, Ensink RJ, Huygen P, Cremers CW, Van Camp G (2000) Mutations in the KCNQ4 K+ channel gene, responsible for autosomal dominant hearing loss, cluster in the channel pore region. Am J Med Genet 93:184–187
Vigil FA, Carver CM, Shapiro MS (2020) Pharmacological manipulation of K (v) 7 channels as a new therapeutic tool for multiple brain disorders. Front Physiol 11:688
Villalba-Galea CA (2020) Modulation of KV7 channel deactivation by PI(4,5)P2. Front Pharmacol 11:895
Vohra J (2007) The long QT syndrome. Heart Lung Circ 16(Suppl 3):S5–S12
Waldegger S (2003) Heartburn: cardiac potassium channels involved in parietal cell acid secretion. Pflugers Arch 446:143–147
Wallace DJ, Chen C, Marley PD (2002) Histamine promotes excitability in bovine adrenal chromaffin cells by inhibiting an M-current. J Physiol 540:921–939
Walsh KB, Kass RS (1988) Regulation of a heart potassium channel by protein kinase A and C. Science 242:67–69
Wang KW, Goldstein SA (1995) Subunit composition of minK potassium channels. Neuron 14:1303–1309
Wang Q, Curran ME, Splawski I, Burn TC, Millholland JM, VanRaay TJ, Shen J, Timothy KW, Vincent GM, de Jager T, Schwartz PJ, Toubin JA, Moss AJ, Atkinson DL, Landes GM, Connors TD, Keating MT (1996) Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet 12:17–23
Wang HS, Pan Z, Shi W, Brown BS, Wymore RS, Cohen IS, Dixon JE, McKinnon D (1998) KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel. Science 282:1890–1893
Wang HS, Brown BS, McKinnon D, Cohen IS (2000) Molecular basis for differential sensitivity of KCNQ and I(Ks) channels to the cognitive enhancer XE991. Mol Pharmacol 57:1218–1223
Wang Z, Li H, Moss AJ, Robinson J, Zareba W, Knilans T, Bowles NE, Towbin JA (2002) Compound heterozygous mutations in KvLQT1 cause Jervell and Lange-Nielsen syndrome. Mol Genet Metab 75:308–316
Wang M, Gamo NJ, Yang Y, Jin LE, Wang XJ, Laubach M, Mazer JA, Lee D, Arnsten AF (2011) Neuronal basis of age-related working memory decline. Nature 476:210–213
Wang J, Yu W, Gao Q, Ju C, Wang K (2020a) Prefrontal inhibition of neuronal Kv7 channels enhances prepulse inhibition of acoustic startle reflex and resilience to hypofrontality. Br J Pharmacol 177:4720–4733
Wang Y, Eldstrom J, Fedida D (2020b) Gating and regulation of KCNQ1 and KCNQ1 + KCNE1 channel complexes. Front Physiol 11:504
Wangemann P (2002) K+ cycling and the endocochlear potential. Hear Res 165:1–9
Warth R, Riedemann N, Bleich M, Van Driessche W, Busch AE, Greger R (1996) The cAMP-regulated and 293B-inhibited K+ conductance of rat colonic crypt base cells. Pflugers Arch 432:81–88
Weckhuysen S, Ivanovic V, Hendrickx R, van Coster R, Hjalgrim H, Moller RS, Gronborg S, Schoonjans AS, Ceulemans B, Heavin SB, Eltze C, Horvath R, Casara G, Pisano T, Giordano L, Rostasy K, Haberlandt E, Albrecht B, Bevot A, Benkel I, Syrbe S, Sheidley B, Guerrini R, Poduri A, Lemke JR, Mandelstam S, Scheffer I, Angriman M, Striano P, Marini C, Suls A, De Jonghe P, Group KS (2013) Extending the KCNQ2 encephalopathy spectrum: clinical and neuroimaging findings in 17 patients. Neurology 81:1697–1703
Wei A, Jegla T, Salkoff L (1996) Eight potassium channel families revealed by the C. elegans genome project. Neuropharmacology 35:805–829
Wei J, Fish FA, Myerburg RJ, Roden DM, George AL Jr (2000) Novel KCNQ1 mutations associated with recessive and dominant congenital long QT syndromes: evidence for variable hearing phenotype associated with R518X. Hum Mutat 15:387–388
Wen H, Levitan IB (2002) Calmodulin is an auxiliary subunit of KCNQ2/3 potassium channels. J Neurosci 22:7991–8001
Werry D, Eldstrom J, Wang Z, Fedida D (2013) Single-channel basis for the slow activation of the repolarizing cardiac potassium current, IKs. Proc Natl Acad Sci U S A 110:E996–E1005
Westhoff M, Murray CI, Eldstrom J, Fedida D (2017) Photo-cross-linking of IKs demonstrates state-dependent interactions between KCNE1 and KCNQ1. Biophys J 113:415–425
Westhoff M, Eldstrom J, Murray CI, Thompson E, Fedida D (2019) I Ks ion-channel pore conductance can result from individual voltage sensor movements. Proc Natl Acad Sci U S A 116:7879–7888
Wickenden AD, Zou A, Wagoner PK, Jegla T (2001) Characterization of KCNQ5/Q3 potassium channels expressed in mammalian cells. Br J Pharmacol 132:381–384
Wladyka CL, Feng B, Glazebrook PA, Schild JH, Kunze DL (2008) The KCNQ/M-current modulates arterial baroreceptor function at the sensory terminal in rats. J Physiol 586:795–802
Wollmuth LP (1994) Mechanism of Ba2+ block of M-like K channels of rod photoreceptors of tiger salamanders. J Gen Physiol 103:45–66
Wrobel E, Tapken D, Seebohm G (2012) The KCNE tango – how KCNE1 interacts with Kv7.1. Front Pharmacol 3:142
Wuttke TV, Seebohm G, Bail S, Maljevic S, Lerche H (2005) The new anticonvulsant retigabine favors voltage-dependent opening of the Kv7.2 (KCNQ2) channel by binding to its activation gate. Mol Pharmacol 67:1009–1017
Xia X, Zhang Q, Jia Y, Shu Y, Yang J, Yang H, Yan Z (2020) Molecular basis and restoration of function deficiencies of Kv7.4 variants associated with inherited hearing loss. Hear Res 388:107884
Xu Q, Minor DL Jr (2009) Crystal structure of a trimeric form of the K(V)7.1 (KCNQ1) A-domain tail coiled-coil reveals structural plasticity and context dependent changes in a putative coiled-coil trimerization motif. Protein Sci 18:2100–2114
Xu T, Nie L, Zhang Y, Mo J, Feng W, Wei D, Petrov E, Calisto LE, Kachar B, Beisel KW, Vazquez AE, Yamoah EN (2007) Roles of alternative splicing in the functional properties of inner ear-specific KCNQ4 channels. J Biol Chem 282:23899–23909
Xu X, Kanda VA, Choi E, Panaghie G, Roepke TK, Gaeta SA, Christini DJ, Lerner DJ, Abbott GW (2009) MinK-dependent internalization of the IKs potassium channel. Cardiovasc Res 82:430–438
Xu Q, Chang A, Tolia A, Minor DL Jr (2013) Structure of a Ca(2+)/CaM:Kv7.4 (KCNQ4) B-helix complex provides insight into M current modulation. J Mol Biol 425:378–394
Yadav G, Jain G, Singh M (2017) Role of flupirtine in reducing preoperative anxiety of patients undergoing craniotomy procedure. Saudi J Anaesth 11:158–162
Yang Y, Sigworth FJ (1998) Single-channel properties of IKs potassium channels. J Gen Physiol 112:665–678
Yang WP, Levesque PC, Little WA, Conder ML, Shalaby FY, Blanar MA (1997) KvLQT1, a voltage-gated potassium channel responsible for human cardiac arrhythmias. Proc Natl Acad Sci U S A 94:4017–4021
Yang WP, Levesque PC, Little WA, Conder ML, Ramakrishnan P, Neubauer MG, Blanar MA (1998) Functional expression of two KvLQT1-related potassium channels responsible for an inherited idiopathic epilepsy. J Biol Chem 273:19419–19423
Young MB, Thomas SA (2014) M1-muscarinic receptors promote fear memory consolidation via phospholipase C and the M-current. J Neurosci 34:1570–1578
Yus-Najera E, Santana-Castro I, Villarroel A (2002) The identification and characterization of a non-continuous calmodulin binding site in non-inactivating voltage-dependent KCNQ potassium channels. J Biol Chem 24:24
Zaczek R, Chorvat RJ, Saye JA, Pierdomenico ME, Maciag CM, Logue AR, Fisher BN, Rominger DH, Earl RA (1998) Two new potent neurotransmitter release enhancers, 10,10-bis(4- pyridinylmethyl)-9(10H)-anthracenone and 10,10-bis(2-fluoro-4- pyridinylmethyl)-9(10H)-anthracenone: comparison to linopirdine. J Pharmacol Exp Ther 285:724–730
Zaika O, Lara LS, Gamper N, Hilgemann DW, Jaffe DB, Shapiro MS (2006) Angiotensin II regulates neuronal excitability via phosphatidylinositol 4,5-bisphosphate-dependent modulation of Kv7 (M-type) K+ channels. J Physiol 575:49–67
Zaika O, Tolstykh GP, Jaffe DB, Shapiro MS (2007) Inositol triphosphate-mediated Ca2+ signals direct purinergic P2Y receptor regulation of neuronal ion channels. J Neurosci 27:8914–8926
Zaydman MA, Cui J (2014) PIP2 regulation of KCNQ channels: biophysical and molecular mechanisms for lipid modulation of voltage-dependent gating. Front Physiol 5:195
Zaydman MA, Silva JR, Delaloye K, Li Y, Liang H, Larsson HP, Shi J, Cui J (2013) Kv7.1 ion channels require a lipid to couple voltage sensing to pore opening. Proc Natl Acad Sci U S A 110:13180–13185
Zaydman MA, Kasimova MA, McFarland K, Beller Z, Hou P, Kinser HE, Liang H, Zhang G, Shi J, Tarek M, Cui J (2014) Domain-domain interactions determine the gating, permeation, pharmacology, and subunit modulation of the IKs ion channel. eLife 3:e03606
Zhang J, Shapiro MS (2012) Activity-dependent transcriptional regulation of M-type (Kv7) K(+) channels by AKAP79/150-mediated NFAT actions. Neuron 76:1133–1146
Zhang J, Shapiro MS (2016) Mechanisms and dynamics of AKAP79/150-orchestrated multi-protein signalling complexes in brain and peripheral nerve. J Physiol 594:31–37
Zhang H, Craciun LC, Mirshahi T, Rohacs T, Lopes CM, Jin T, Logothetis DE (2003) PIP2 activates KCNQ channels, and its hydrolysis underlies receptor-mediated inhibition of M currents. Neuron 37:963–975
Zhang J, Bal M, Bierbower S, Zaika O, Shapiro MS (2011) AKAP79/150 signal complexes in G-protein modulation of neuronal ion channels. J Neurosci 31:7199–7211
Zhang J, Chen SR, Chen H, Pan HL (2018) RE1-silencing transcription factor controls the acute-to-chronic neuropathic pain transition and Chrm2 receptor gene expression in primary sensory neurons. J Biol Chem 293:19078–19091
Zhang F, Gigout S, Liu Y, Wang Y, Hao H, Buckley NJ, Zhang H, Wood IC, Gamper N (2019) Repressor element 1-silencing transcription factor drives the development of chronic pain states. Pain 160:2398–2408
Zhang D, Men H, Zhang L, Gao X, Wang J, Li L, Zhu Q, Zhang H, Jia Z (2020) Inhibition of M/K(v)7 currents contributes to chloroquine-induced itch in mice. Front Mol Neurosci 13:105
Zhao C, Su M, Wang Y, Li X, Zhang Y, Du X, Zhang H (2017) Selective modulation of K(+) channel Kv7.4 significantly affects the excitability of DRN 5-HT neurons. Front Cell Neurosci 11:405
Zheng Q, Fang D, Liu M, Cai J, Wan Y, Han JS, Xing GG (2013) Suppression of KCNQ/M (Kv7) potassium channels in dorsal root ganglion neurons contributes to the development of bone cancer pain in a rat model. Pain 154:434–448
Zwierzyńska E, Krupa-Burtnik A, Pietrzak B (2017) The possibility of adverse effect of Kv7-channel opener retigabine on memory processes in rats. Epilepsy Behav E&B 75:170–175
Acknowledgments
The work in our laboratories is supported by Wellcome Trust (212302/Z/18/Z to NG), Medical Research Council (MR/P015727/1 to NG & FJ), Biotechnology and Biological Sciences Research Council (BB/R003068/1, BB/R02104X/1 to NG) and National Natural Science Foundation of China (81871027 to HG & NG).
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Jones, F., Gamper, N., Gao, H. (2021). Kv7 Channels and Excitability Disorders. In: Gamper, N., Wang, K. (eds) Pharmacology of Potassium Channels. Handbook of Experimental Pharmacology, vol 267. Springer, Cham. https://doi.org/10.1007/164_2021_457
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