Role of calmodulin in neuronal Kv7/KCNQ potassium channels and epilepsy

Abstract

Neuronal Kv7/KCNQ channels are critical regulators of neuronal excitability since they potently suppress repetitive firing of action potentials. These voltage-dependent potassium channels are composed mostly of Kv7.2 / KCNQ2 and Kv7.3 / KCNQ3 subunits that show overlapping distribution throughout the brain and in the peripheral nervous system. They are also called ‘M-channels’ since their inhibition by muscarinic agonists leads to a profound increase in action potential firing. Consistent with their ability to suppress seizures and attenuate chronic inflammatory and neuropathic pain, mutations in the KCNQ2 and KCNQ3 genes are associated with benign familial neonatal convulsions, a dominantly-inherited epilepsy in infancy. Recently, de novo mutations in the KCNQ2 gene have been linked to early onset epileptic encephalopathy. Notably, some of these mutations are clustered in a region of the intracellular cytoplasmic tail of Kv7.2 that interacts with a ubiquitous calcium sensor, calmodulin. In this review, we highlight the recent advances in understanding the role of calmodulin in modulating physiological function of neuronal Kv7 channels including their biophysical properties, assembly, and trafficking. We also summarize recent studies that have investigated functional impact of epilepsy-associated mutations localized to the calmodulin binding domains of Kv7.2.

Key words： calmodulin; Kv7; KCNQ; epilepsy; action potential; M-channel

Acknowledgements

I thank John Cavaretta for his helpful comments on this manuscript.

Compliance with ethics guidelines

Hee Jung Chung declares that she has no conflict of interest. This review article does not contain any studies with human or animal subjects performed by the any of the authors.

References

1 AivarP, Fernández-OrthJ, Gomis-PerezC, AlberdiA, AlaimoA, RodríguezM S, GiraldezT, MirandaP, AresoP, VillarroelA (2012). Surface expression and subunit specific control of steady protein levels by the Kv7.2 helix A-B linker. PLoS One, 7(10): e47263

PMID

2 AlaimoA, AlberdiA, Gomis-PerezC, Fernandez-OrthJ, Gomez-PosadaJ C, AresoP, VillarroelA (2012). Cooperativity between calmodulin binding sites in Kv7.2 channels. J Cell Sci

PMID

3 AlaimoA, Gómez-PosadaJ C, AivarP, EtxeberríaA, Rodriguez-AlfaroJ A, AresoP, VillarroelA (2009). Calmodulin activation limits the rate of KCNQ2 K⁺ channel exit from the endoplasmic reticulum. J Biol Chem, 284(31): 20668-20675

PMID

4 AlfonsoI, HahnJ S, PapazianO, MartinezY L, ReyesM A, AicardiJ (1997). Bilateral tonic-clonic epileptic seizures in non-benign familial neonatal convulsions. Pediatr Neurol, 16(3): 249-251

PMID

5 BalM, ZhangJ, HernandezCC, ZaikaO, ShapiroMS (2010) Ca²⁺/calmodulin disrupts AKAP79/150 interactions with KCNQ (M-Type) K⁺ channels. The Journal of neuroscience: the official journal of the Society for Neuroscience30: 2311-2323.

6 Blackburn-MunroG, JensenB S (2003). The anticonvulsant retigabine attenuates nociceptive behaviours in rat models of persistent and neuropathic pain. Eur J Pharmacol, 460(2-3): 109-116

PMID

7 BorgattiR, ZuccaC, CavalliniA, FerrarioM, PanzeriC, CastaldoP, SoldovieriM V, BaschirottoC, BresolinN, Dalla BernardinaB, TaglialatelaM, BassiM T (2004). A novel mutation in KCNQ2 associated with BFNC, drug resistant epilepsy, and mental retardation. Neurology, 63(1): 57-65

PMID

8 BrownD A, PassmoreG M (2009). Neural KCNQ (Kv7) channels. Br J Pharmacol, 156(8): 1185-1195

PMID

9 ChoveauF S, BierbowerS M, ShapiroM S (2012). Pore helix-S6 interactions are critical in governing current amplitudes of KCNQ3 K+ channels. Biophys J, 102(11): 2499-2509

PMID

10 ChungH J, JanY N, JanL Y (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(23): 8870-8875

PMID

11 ClarkB D, GoldbergE M, RudyB (2009). Electrogenic tuning of the axon initial segment. Neuroscientist, 15(6): 651-668

PMID

12 CooperE C, HarringtonE, JanY N, JanL Y (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

13 CoppolaG, CastaldoP, Miraglia del GiudiceE, BelliniG, GalassoF, SoldovieriM V, AnzaloneL, SferroC, AnnunziatoL, PascottoA, TaglialatelaM (2003). A novel KCNQ2 K⁺ channel mutation in benign neonatal convulsions and centrotemporal spikes. Neurology, 61(1): 131-134

PMID

14 DahimèneS, AlcoléaS, NaudP, JourdonP, EscandeD, BrasseurR, ThomasA, BaróI, MérotJ (2006). The N-terminal juxtamembranous domain of KCNQ1 is critical for channel surface expression: implications in the Romano-Ward LQT1 syndrome. Circ Res, 99(10): 1076-1083

PMID

15 DaileyJ W, CheongJ H, KoK H, Adams-CurtisL E, JobeP C (1995). Anticonvulsant properties of D-20443 in genetically epilepsy-prone rats: prediction of clinical response. Neurosci Lett, 195(2): 77-80

PMID

16 DedekK, FuscoL, TeloyN, SteinleinO K (2003). Neonatal convulsions and epileptic encephalopathy in an Italian family with a missense mutation in the fifth transmembrane region of KCNQ2. Epilepsy Res, 54(1): 21-27

PMID

17 DedekK, KunathB, KananuraC, ReunerU, JentschT J, SteinleinO K (2001). Myokymia and neonatal epilepsy caused by a mutation in the voltage sensor of the KCNQ2 K+ channel. Proc Natl Acad Sci U S A, 98(21): 12272-12277

PMID

18 DelmasP, BrownD A (2005). Pathways modulating neural KCNQ/M (Kv7) potassium channels. Nat Rev Neurosci, 6(11): 850-862

PMID

19 DenckerD, DiasR, PedersenM L, HusumH (2008). Effect of the new antiepileptic drug retigabine in a rodent model of mania. Epilepsy Behav, 12(1): 49-53

PMID

20 DevauxJ J, KleopaK A, CooperE C, SchererS S (2004). KCNQ2 is a nodal K⁺ channel. J Neurosci, 24: 1236-1244

21 EtxeberriaA, AivarP, Rodriguez-AlfaroJ A, AlaimoA, VillaceP, Gomez-PosadaJ C, AresoP, VillarroelA (2008). Calmodulin regulates the trafficking of KCNQ2 potassium channels. FASEB J, 22: 1135-1143

22 EtxeberriaA, Santana-CastroI, RegaladoMP, AivarP, VillarroelA (2004). Three mechanisms underlie KCNQ2/3 heteromeric potassium M-channel potentiation. J Neurosci, 24: 9146-9152

23 EtzioniA, SiloniS, ChikvashvilliD, StrulovichR, SachyaniD, RegevN, Greitzer-AntesD, HirschJ A, LotanI (2011). Regulation of neuronal M-channel gating in an isoform-specific manner: functional interplay between calmodulin and syntaxin 1A. J Neurosci, 31: 14158-14171

24 FordC P, StemkowskiPL, LightP E, SmithP A (2003). Experiments to test the role of phosphatidylinositol 4,5-bisphosphate in neurotransmitter-induced M-channel closure in bullfrog sympathetic neurons. J Neurosci, 234931-4941

25 GamperN, LiY, ShapiroM S (2005). Structural requirements for differential sensitivity of KCNQ K⁺ channels to modulation by Ca²⁺/calmodulin. Mol Biol Cell, 16(8): 3538-3551

PMID

26 GamperN, ShapiroM S (2003). Calmodulin mediates Ca²⁺-dependent modulation of M-type K⁺ channels. J Gen Physiol, 122(1): 17-31

PMID

27 GamperN, ShapiroM S (2007). Regulation of ion transport proteins by membrane phosphoinositides. Nat Rev Neurosci, 8(12): 921-934

PMID

28 Gómez-PosadaJ C, AivarP, AlberdiA, AlaimoA, EtxeberríaA, Fernández-OrthJ, ZamalloaT, Roura-FerrerM, VillaceP, AresoP, CasisO, VillarroelA (2011). Kv7 channels can function without constitutive calmodulin tethering. PLoS One, 6(9): e25508

PMID

29 GuN, VervaekeK, HuH, StormJ F (2005). Kv7/KCNQ/M and HCN/h, but not KCa2/SK channels, contribute to the somatic medium after-hyperpolarization and excitability control in CA1 hippocampal pyramidal cells. J Physiol, 566(Pt 3): 689-715

PMID

30 GunthorpeM J, LargeC H, SankarR (2012). The mechanism of action of retigabine (ezogabine), a first-in-class K⁺ channel opener for the treatment of epilepsy. Epilepsia, 53(3): 412-424

PMID

31 HadleyJ K, PassmoreG M, TatulianL, Al-QatariM, YeF, WickendenA D, BrownD A (2003) Stoichiometry of expressed KCNQ2/KCNQ3 potassium channels and subunit composition of native ganglionic M channels deduced from block by tetraethylammonium. J Neurosci, 23: 5012-5019

32 HaitinY, AttaliB (2008). The C-terminus of Kv7 channels: a multifunctional module. J Physiol, 586(7): 1803-1810

PMID

33 HansenH H, AndreasenJ T, WeikopP, MirzaN, Scheel-KrügerJ, MikkelsenJ D (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(1-3): 77-88

PMID

34 HernandezC C, ZaikaO, ShapiroM S (2008). 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(3): 361-381

PMID

35 HigashidaH, HoshiN, ZhangJ S, YokoyamaS, HashiiM, JinD, NodaM, RobbinsJ (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(3): 231-234

PMID

36 HoeflichK P, IkuraM (2002). Calmodulin in action: diversity in target recognition and activation mechanisms. Cell, 108(6): 739-742

PMID

37 HoshiN, LangebergL K, ScottJ D (2005). Distinct enzyme combinations in AKAP signalling complexes permit functional diversity. Nat Cell Biol, 7(11): 1066-1073

PMID

38 HoshiN, ZhangJ S, OmakiM, TakeuchiT, YokoyamaS, WanaverbecqN, LangebergL K, YonedaY, ScottJ D, BrownD A, HigashidaH (2003). AKAP150 signaling complex promotes suppression of the M-current by muscarinic agonists. Nat Neurosci, 6(6): 564-571

PMID

39 HowardA L, NeuA, MorganR J, EchegoyenJ C, SolteszI (2007a). Opposing modifications in intrinsic currents and synaptic inputs in post-traumatic mossy cells: evidence for single-cell homeostasis in a hyperexcitable network. J Neurophysiol, 97(3): 2394-2409

PMID

40 HowardR J, ClarkK A, HoltonJ M, MinorD L Jr (2007b). Structural insight into KCNQ (Kv7) channel assembly and channelopathy. Neuron, 53(5): 663-675

PMID

41 KorsgaardM P, HartzB P, BrownW D, AhringP K, StrøbaekD, MirzaN R (2005). Anxiolytic effects of Maxipost (BMS-204352) and retigabine via activation of neuronal Kv7 channels. J Pharmacol Exp Ther, 314(1): 282-292

PMID

42 KosenkoA, KangS, SmithI M, GreeneD L, LangebergL K, ScottJ D, HoshiN (2012). Coordinated signal integration at the M-type potassium channel upon muscarinic stimulation. EMBO J, 31(14): 3147-3156

PMID

43 KwanP, BrodieM J (2000). Epilepsy after the first drug fails: substitution or add-on? Seizure, 9(7): 464-468

PMID

44 LaiH C, JanL Y (2006). The distribution and targeting of neuronal voltage-gated ion channels. Nat Rev Neurosci, 7(7): 548-562

PMID

45 LargeC H, SokalD M, NehligA, GunthorpeM J, SankarR, CreanC S, VanlandinghamK E, WhiteH S (2012). The spectrum of anticonvulsant efficacy of retigabine (ezogabine) in animal models: implications for clinical use. Epilepsia, 53(3): 425-436

PMID

46 LercheH, BiervertC, AlekovA K, SchleithoffL, LindnerM, KlingerW, BretschneiderF, MitrovicN, Jurkat-RottK, BodeH, Lehmann-HornF, SteinleinO K (1999). A reduced K+ current due to a novel mutation in KCNQ2 causes neonatal convulsions. Ann Neurol, 46(3): 305-312

PMID

47 LiY, GamperN, HilgemannDW, ShapiroMS (2005). Regulation of Kv7 (KCNQ) K+ channel open probability by phosphatidylinositol 4,5-bisphosphate. J Neurosci, 25: 9825-9835

48 LiuW, DevauxJ J (2014). Calmodulin orchestrates the heteromeric assembly and the trafficking of KCNQ2/3 (Kv7.2/3) channels in neurons. Mol Cell Neurosci, 58: 40-52

PMID

49 MaljevicS, WuttkeT V, LercheH (2008). Nervous system KV7 disorders: breakdown of a subthreshold brake. J Physiol, 586(7): 1791-1801

PMID

50 MartireM, CastaldoP, D'AmicoM, PreziosiP, AnnunziatoL, TaglialatelaM (2004). M channels containing KCNQ2 subunits modulate norepinephrine, aspartate, and GABA release from hippocampal nerve terminals. J Neurosci, 24: 592-597

51 MoulardB, PicardF, le HellardS, AgulhonC, WeilandS, FavreI, BertrandS, MalafosseA, BertrandD (2001). Ion channel variation causes epilepsies. Brain Res Brain Res Rev, 36(2-3): 275-284

PMID

52 OhtaharaS, YamatogiY (2006). Ohtahara syndrome: with special reference to its developmental aspects for differentiating from early myoclonic encephalopathy. Epilepsy Res, 70(Suppl 1): S58-S67

PMID

53 OrhanG, BockM, SchepersD, IlinaE I, ReichelS N, LofflerH, JezutkovicN, WeckhuysenS, MandelstamS, SulsA, DankerT, GuentherE, SchefferI E, JongheP D, LercheH, MaljevicS (2013). Dominant-negative Effects of KCNQ2 mutations are associated with epileptic encephalopathy. Ann Neurol, 75(3): 382-394

54 PanZ, KaoT, HorvathZ, LemosJ, SulJ Y, CranstounS D, BennettV, SchererS S, CooperE C (2006). A common ankyrin-G-based mechanism retains KCNQ and NaV channels at electrically active domains of the axon. J Neurosci, 26: 2599-2613

55 PassmoreG M, SelyankoA A, MistryM, Al-QatariM, MarshS J, MatthewsE A, DickensonAH, BrownT A, BurbidgeS A, MainM, BrownD A (2003). KCNQ/M currents in sensory neurons: significance for pain therapy. J Neurosci, 23: 7227-7236

56 PeretzA, SheininA, YueC, Degani-KatzavN, GiborG, NachmanR, GopinA, TamE, ShabatD, YaariY, AttaliB (2007). Pre- and postsynaptic activation of M-channels by a novel opener dampens neuronal firing and transmitter release. J Neurophysiol, 97(1): 283-295

PMID

57 PetersH C, HuH, PongsO, StormJ F, IsbrandtD (2005). Conditional transgenic suppression of M channels in mouse brain reveals functions in neuronal excitability, resonance and behavior. Nat Neurosci, 8(1): 51-60

PMID

58 PsenkaT M, HoldenK R (1996). Benign familial neonatal convulsions; psychosocial adjustment to the threat of recurrent seizures. Seizure, 5(3): 243-245

PMID

59 RasmussenH B, Frøkjaer-JensenC, JensenC S, JensenH S, JørgensenN K, MisonouH, TrimmerJ S, OlesenS P, SchmittN (2007). Requirement of subunit co-assembly and ankyrin-G for M-channel localization at the axon initial segment. J Cell Sci, 120(Pt 6): 953-963

PMID

60 RegevN, Degani-KatzavN, KorngreenA, EtzioniA, SiloniS, AlaimoA, ChikvashviliD, VillarroelA, AttaliB, LotanI (2009). Selective interaction of syntaxin 1A with KCNQ2: possible implications for specific modulation of presynaptic activity. PLoS One, 4(8): e6586

PMID

61 RichardsM C, HeronS E, SpendloveH E, SchefferI E, GrintonB, BerkovicS F, MulleyJ C, DavyA (2004). Novel mutations in the KCNQ2 gene link epilepsy to a dysfunction of the KCNQ2-calmodulin interaction. J Med Genet, 41(3): e35

PMID

62 RobbinsJ (2001). KCNQ potassium channels: physiology, pathophysiology, and pharmacology. Pharmacol Ther, 90(1): 1-19

PMID

63 RocheJ P, WestenbroekR, SoromA J, HilleB, MackieK, ShapiroM S (2002). Antibodies and a cysteine-modifying reagent show correspondence of M current in neurons to KCNQ2 and KCNQ3 K+ channels. Br J Pharmacol, 137(8): 1173-1186

PMID

64 RostockA, ToberC, RundfeldtC, BartschR, EngelJ, PolymeropoulosE E, KutscherB, LöscherW, HönackD, WhiteH S, WolfH H (1996). D-23129: a new anticonvulsant with a broad spectrum activity in animal models of epileptic seizures. Epilepsy Res, 23(3): 211-223

PMID

65 SaitsuH, KatoM, KoideA, GotoT, FujitaT, NishiyamaK, TsurusakiY, DoiH, MiyakeN, HayasakaK, MatsumotoN (2012). Whole exome sequencing identifies KCNQ2 mutations in Ohtahara syndrome. Ann Neurol, 72(2): 298-300

PMID

66 SchmittB, WohlrabG, SanderT, SteinleinO K, HajnalB L (2005). Neonatal seizures with tonic clonic sequences and poor developmental outcome. Epilepsy Res, 65(3): 161-168

PMID

67 SchroederB C, KubischC, SteinV, JentschT J (1998). Moderate loss of function of cyclic-AMP-modulated KCNQ2/KCNQ3 K+ channels causes epilepsy. Nature, 396(6712): 687-690

PMID

68 SchwakeM, AthanasiaduD, BeimgrabenC, BlanzJ, BeckC, JentschTJ, SaftigP, FriedrichT (2006). Structural determinants of M-type KCNQ (Kv7) K⁺ channel assembly. J Neurosci, 26: 3757-3766

69 SchwakeM, JentschT J, FriedrichT (2003). A carboxy-terminal domain determines the subunit specificity of KCNQ K+ channel assembly. EMBO Rep, 4(1): 76-81

PMID

70 SchwakeM, PuschM, KharkovetsT, JentschT J (2000). Surface expression and single channel properties of KCNQ2/KCNQ3, M-type K+ channels involved in epilepsy. J Biol Chem, 275(18): 13343-13348

PMID

71 SchwarzJ R, GlassmeierG, CooperE C, KaoT C, NoderaH, TabuenaD, KajiR, BostockH (2006). KCNQ channels mediate IKs, a slow K+ current regulating excitability in the rat node of Ranvier. J Physiol, 573(Pt 1): 17-34

PMID

72 SelyankoA A, BrownD A (1996). Intracellular calcium directly inhibits potassium M channels in excised membrane patches from rat sympathetic neurons. Neuron, 16(1): 151-162

PMID

73 ShahM M, MiglioreM, BrownD A (2011). Differential effects of Kv7 (M-) channels on synaptic integration in distinct subcellular compartments of rat hippocampal pyramidal neurons. J Physiol, 589(Pt 24): 6029-6038

PMID

74 ShahM M, MiglioreM, ValenciaI, CooperE C, BrownD A (2008). Functional significance of axonal Kv7 channels in hippocampal pyramidal neurons. Proc Natl Acad Sci U S A, 105(22): 7869-7874

PMID

75 ShahM, MistryM, MarshS J, BrownD A, DelmasP (2002). Molecular correlates of the M-current in cultured rat hippocampal neurons. J Physiol, 544(Pt 1): 29-37

PMID

76 ShahidullahM, SantarelliL C, WenH, LevitanI B (2005). Expression of a calmodulin-binding KCNQ2 potassium channel fragment modulates neuronal M-current and membrane excitability. Proc Natl Acad Sci U S A, 102(45): 16454-16459

PMID

77 SinghNA, WestenskowP, CharlierC, PappasC, LeslieJ, DillonJ, AndersonVE, SanguinettiMC, LeppertMF (2003) KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: expansion of the functional and mutation spectrum. Brain, 126: 2726-2737

78 SoldovieriM V, Boutry-KryzaN, MilhM, DoummarD, HeronB, BourelE, AmbrosinoP, MiceliF, De MariaM, DorisonN, AuvinS, EchenneB, OertelJ, RiquetA, LambertL, GerardM, RoubergueA, CalenderA, MignotC, TaglialatelaM, LescaG (2014). Novel KCNQ2 and KCNQ3 mutations in a large cohort of families with benign neonatal epilepsy: first evidence for an altered channel regulation by syntaxin-1A. Hum Mutat, 35(3): 356-367

PMID

79 SoldovieriM V, CastaldoP, IodiceL, MiceliF, BarreseV, BelliniG, Miraglia del GiudiceE, PascottoA, BonattiS, AnnunziatoL, TaglialatelaM (2006). Decreased subunit stability as a novel mechanism for potassium current impairment by a KCNQ2 C terminus mutation causing benign familial neonatal convulsions. J Biol Chem, 281(1): 418-428

PMID

80 SoldovieriM V, MiceliF, TaglialatelaM (2011). Driving with no brakes: molecular pathophysiology of Kv7 potassium channels. Physiology (Bethesda), 26(5): 365-376

PMID

81 SongA H, WangD, ChenG, LiY, LuoJ, DuanS, PooM M (2009). A selective filter for cytoplasmic transport at the axon initial segment. Cell, 136(6): 1148-1160

PMID

82 SuhB C, HilleB (2002). Recovery from muscarinic modulation of M current channels requires phosphatidylinositol 4,5-bisphosphate synthesis. Neuron, 35(3): 507-520

PMID

83 SuhB C, HilleB (2007). Regulation of KCNQ channels by manipulation of phosphoinositides. J Physiol, 582(Pt 3): 911-916

PMID

84 SuhB C, HorowitzL F, HirdesW, MackieK, HilleB (2004). Regulation of KCNQ2/KCNQ3 current by G protein cycling: the kinetics of receptor-mediated signaling by Gq. J Gen Physiol, 123(6): 663-683

PMID

85 SurtiT S, JanL Y (2005). A potassium channel, the M-channel, as a therapeutic target. Curr Opin Investig Drugs, 6(7): 704-711

PMID

86 ToberC, RostockA, RundfeldtC, BartschR (1996). D-23129: a potent anticonvulsant in the amygdala kindling model of complex partial seizures. Eur J Pharmacol, 303(3): 163-169

PMID

87 TzingounisA V, HeidenreichM, KharkovetsT, SpitzmaulG, JensenH S, NicollR A, JentschT J (2010). The KCNQ5 potassium channel mediates a component of the afterhyperpolarization current in mouse hippocampus. Proc Natl Acad Sci U S A, 107(22): 10232-10237

PMID

88 TzingounisA V, NicollR A (2008). Contribution of KCNQ2 and KCNQ3 to the medium and slow afterhyperpolarization currents. Proc Natl Acad Sci U S A, 105(50): 19974-19979

PMID

89 WangH S, PanZ, ShiW, BrownB S, WymoreR S, CohenI S, DixonJ E, McKinnonD (1998). KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel. Science, 282(5395): 1890-1893

PMID

90 WatanabeH, NagataE, KosakaiA, NakamuraM, YokoyamaM, TanakaK, SasaiH (2000). Disruption of the epilepsy KCNQ2 gene results in neural hyperexcitability. J Neurochem, 75(1): 28-33

PMID

91 WeckhuysenS, MandelstamS, SulsA, AudenaertD, DeconinckT, ClaesL R, DeprezL, SmetsK, HristovaD, YordanovaI, JordanovaA, CeulemansB, JansenA, HasaertsD, RoelensF, LagaeL, YendleS, StanleyT, HeronS E, MulleyJ C, BerkovicS F, SchefferI E, de JongheP (2012). KCNQ2 encephalopathy: emerging phenotype of a neonatal epileptic encephalopathy. Ann Neurol, 71(1): 15-25

PMID

92 WenH, LevitanIB (2002) Calmodulin is an auxiliary subunit of KCNQ2/3 potassium channels. J Neurosci, 22: 7991-8001

93 WinksJS, HughesS, FilippovA K, TatulianL, AbogadieF C, BrownD A, MarshS J (2005). Relationship between membrane phosphatidylinositol-4,5-bisphosphate and receptor-mediated inhibition of native neuronal M channels. J Neurosci, 25: 3400-3413

94 WongW, ScottJ D (2004). AKAP signalling complexes: focal points in space and time. Nat Rev Mol Cell Biol, 5(12): 959-970

PMID

95 WuttkeT V, Jurkat-RottK, PaulusW, GarncarekM, Lehmann-HornF, LercheH (2007). Peripheral nerve hyperexcitability due to dominant-negative KCNQ2 mutations. Neurology, 69(22): 2045-2053

PMID

96 XuQ, ChangA, ToliaA, MinorD L Jr (2013). Structure of a Ca(2+)/CaM:Kv7.4 (KCNQ4) B-helix complex provides insight into M current modulation. J Mol Biol, 425(2): 378-394

PMID

97 YueC, YaariY (2004) KCNQ/M channels control spike afterdepolarization and burst generation in hippocampal neurons. J Neurosci, 24: 4614-4624

98 YueC, YaariY (2006) Axo-somatic and apical dendritic Kv7/M channels differentially regulate the intrinsic excitability of adult rat CA1 pyramidal cells. J Neurophysiol, 95(6): 3480-3495

99 Yus-NajeraE, Santana-CastroI, VillarroelA (2002). The identification and characterization of a noncontinuous calmodulin-binding site in noninactivating voltage-dependent KCNQ potassium channels. J Biol Chem, 277(32): 28545-28553

PMID

100 ZaikaO, TolstykhG P, JaffeD B, ShapiroM S (2007) Inositol triphosphate-mediated Ca²⁺ signals direct purinergic P2Y receptor regulation of neuronal ion channels. J Neurosci, 27: 8914-8926

101 ZhangH, CraciunL C, MirshahiT, RohácsT, LopesC M, JinT, LogothetisD E (2003). PIP(2) activates KCNQ channels, and its hydrolysis underlies receptor-mediated inhibition of M currents. Neuron, 37(6): 963-975

PMID