pp 1-29 | Cite as

Gating Pore Currents in Sodium Channels

Part of the Handbook of Experimental Pharmacology book series


Voltage-gated sodium channels belong to the superfamily of voltage-gated cation channels. Their structure is based on domains comprising a voltage sensor domain (S1–S4 segments) and a pore domain (S5–S6 segments). Mutations in positively charged residues of the S4 segments may allow protons or cations to pass directly through the gating pore constriction of the voltage sensor domain; these anomalous currents are referred to as gating pore or omega (ω) currents. In the skeletal muscle disorder hypokalemic periodic paralysis, and in arrhythmic dilated cardiomyopathy, inherited mutations of S4 arginine residues promote omega currents that have been shown to be a contributing factor in the pathogenesis of these sodium channel disorders. Characterization of gating pore currents in these channelopathies and with artificial mutations has been possible by measuring the voltage-dependence and selectivity of these leak currents. The basis of gating pore currents and the structural basis of S4 movement through the gating pore has also been studied extensively with molecular dynamics. These simulations have provided valuable insight into the nature of S4 translocation and the physical basis for the effects of mutations that promote permeation of protons or cations through the gating pore.


Arrhythmic dilated cardiomyopathy Gating pore Hypokalemic periodic paralysis Molecular dynamics Omega current Sodium channel 


  1. Allen MP, Tildesley DJ (1987) Computer simulation of liquids. Clarendon Press, OxfordMATHGoogle Scholar
  2. Armstrong CM, Bezanilla F (1973) Currents related to movement of the gating particles of the sodium channels. Nature 242(5398):459–461ADSPubMedCrossRefGoogle Scholar
  3. Banjeree A, MacKinnon R (2008) Inferred motions of the S3a helix during voltage-dependent K+ channel gating. J Mol Biol 381(3):569–580.  https://doi.org/10.1016/jmb.2008.06.010. CrossRefGoogle Scholar
  4. Beckermann TM, McLeod K, Murday V, Potet F, George AL Jr (2014) Novel SCN5A mutation in amiodarone-responsive multifocal ventricular ectopy-associated cardiomyopathy. Heart Rhythm 11(8):1446–1453.  https://doi.org/10.1016/j.hrthm.2014.04.042 PubMedPubMedCentralCrossRefGoogle Scholar
  5. Bendahhou S, Cummins TR, Griggs RC, Fu Y-H, Ptacek LJ (2001) Sodium channel inactivation defects are associated with acetazolamide-exacerbated hypokalemic periodic paralysis. Ann Neurol 50(3):417–420PubMedCrossRefGoogle Scholar
  6. Bezzina CR, Rook MB, Groenewegen A, Herfst LJ, van der Wal AC, Lam J, Jongsma HJ, Wilde AM, Mannens MMAM (2003) Compound heterozygosity for mutations (W156X and R225W) in SCN5A associated with severe cardiac conduction disturbances and degenerative changes in the conduction system. Circ Res 92:159–168PubMedCrossRefGoogle Scholar
  7. Bezzina CR, Lahoruchi N, Priori SG (2015) Genetics of sudden cardiac death. Circ Res 116:1919–1936. https://doi.org/10.1161/CIRCRESAHA. 116.304030 PubMedCrossRefGoogle Scholar
  8. Bukauskas FF, Peracchia C (1997) Two distinct gating mechanisms in gap junction channels: C02-sensitive and voltage-sensitive. Biophys J 72:2137–2142PubMedPubMedCentralCrossRefGoogle Scholar
  9. Bukauskas FF, Bukauskiene A, Bennett MVL, Verselis V (2001) Gating properties of gap junction channels assembled from connexin43 and connexin43 fused with green fluorescent protein. Biophys J 81:137–152PubMedPubMedCentralCrossRefGoogle Scholar
  10. Bulman DE, Scoggan KA, van Oene MD, Nicolle MW, Hahn AF, Tollar LL, Ebers GC (1999) A novel sodium channel mutation in a family with hypokalemic periodic paralysis. Neurology 53:1932–1936PubMedCrossRefGoogle Scholar
  11. Burge JA, Hanna MG (2012) Novel insights into the pathomechanisms of skeletal muscle channelopathies. Curr Neurol Neurosci Rep 12(1):62–69.  https://doi.org/10.1007/s11910-011-0238-3 PubMedCrossRefGoogle Scholar
  12. Campos FV, Chanda B, Roux B, Bezanilla F (2007) Two atomic constraints unambiguously position the S4 segment relative to S1 and S2 segments in the closed state of the Shaker K channel. Proc Natl Acad Sci U S A 104(19):7904–7909ADSPubMedPubMedCentralCrossRefGoogle Scholar
  13. Cannon SC (2007) Physiologic principles underlying ion channelopathies. Neurotherapeutics 4(2):174–183PubMedCrossRefGoogle Scholar
  14. Cannon SC (2010) Voltage-sensor mutations in channelopathies of skeletal muscle. J Physiol 588(11):1887–1895.  https://doi.org/10.1113/jphysiol.2010.186874 PubMedPubMedCentralCrossRefGoogle Scholar
  15. Cannon SC (2015) Channelopathies of skeletal muscle excitability. Compr Physiol 5(2):761–790.  https://doi.org/10.1002/cphy.c140062 PubMedPubMedCentralCrossRefGoogle Scholar
  16. Cannon SC, Brown RH Jr, Corey DP (1993) Theoretical reconstruction of myotonia and paralysis caused by incomplete inactivation of sodium channels. Biophys J 65:270–288PubMedPubMedCentralCrossRefGoogle Scholar
  17. Carle T, Lhuillier L, Luce S, Sternberg D, Devuyst O, Fontaine B, Tabti N (2006) Gating defects of a novel Na+ channel mutant causing hypokalemic periodic paralysis. Biochem Biophys Res Commun 348:653–661.  https://doi.org/10.1016/j.bbrc.2006.07.101 PubMedCrossRefGoogle Scholar
  18. Catterall WA (1986) Molecular properties of voltage-sensitive sodium channels. Annu Rev Biochem 55:953–985PubMedCrossRefGoogle Scholar
  19. Cha A, Ruben PC, George AL Jr, Fujimoto E, Bezanilla F (1999) Voltage sensors in domains III and IV, but not I and II, are immobilized by Na+ channel fast inactivation. Neuron 22(1):73–87PubMedCrossRefGoogle Scholar
  20. Cheng J, Morales A, Siegfried JD, Li D, Norton N, Song J, Gonzalez-Quintana J, Makielski JC, Hershberger RE (2010) SCN5A rare variants in familial dilated cardiomyopathy decrease peak sodium current depending on the common polymorphism H558R and common splice variant Q1077del. Clin Transl Sci 3:287–294.  https://doi.org/10.1111/j.1752-8062.01000249.x. PubMedPubMedCentralCrossRefGoogle Scholar
  21. Cheng C-J, Lin S-H, Lo Y-F, Yang S-S, Hsu Y-J, Cannon SC, Huang C-L (2011) Identification and functional characterization of Kir2.6 mutations associated with non-familial hypokalemic periodic paralysis. J Biol Chem 286(31):27425–27435.  https://doi.org/10.1074/jbc.M111.249656 PubMedPubMedCentralCrossRefGoogle Scholar
  22. Cheng C-J, Kuo E, Huang C-L (2013) Extracellular potassium homeostasis: insights from hypokalemic periodic paralysis. Semin Nephrol 33(3):237–247.  https://doi.org/10.1016/j.semnephrol.2013.04.004 PubMedPubMedCentralCrossRefGoogle Scholar
  23. Chockalingham P, Wilde A (2012) The multifaceted cardiac sodium channel and its clinical implications. Heart 98(17):1318–1324.  https://doi.org/10.1136/heartjnl-2012-301784 CrossRefGoogle Scholar
  24. Delemotte L, Treptow W, Klein ML, Tarek M (2010) Effect of sensor domain mutations on the properties of voltage-gated ion channels: molecular dynamics studies of the potassium channel Kv1.2. Biophys J 99(9):L72–L74.  https://doi.org/10.1016/bpj.2010.08.069. PubMedPubMedCentralCrossRefGoogle Scholar
  25. Delemotte L, Tarek M, Klein ML, Amaral C, Treptow W (2011) Intermediate states of the Kv1.2 voltage sensor from atomistic molecular dynamics simulations. Proc Natl Acad Sci U S A 108(15):6109–6114.  https://doi.org/10.1073/pnas.1102724108 ADSPubMedPubMedCentralCrossRefGoogle Scholar
  26. Egelman EH (2016) The current revolution in Cryo-EM. Biophys J 110:1008–1012.  https://doi.org/10.1016/j.bpj.2016.02.001 PubMedPubMedCentralCrossRefGoogle Scholar
  27. Fabiato A, Fabiato F (1978) Effects of pH on the myofilaments and the sarcoplasmic reticulum of skinned cells from cardiac and skeletal muscles. J Physiol 276:233–255PubMedPubMedCentralCrossRefGoogle Scholar
  28. Fan C, Lehmann-Horn F, Weber MA, Bednarz M, Groome JR, Jonsson MK, Jurkat-Rott K (2013) Transient compartment-like syndrome and normokalemic periodic paralysis due to a Ca(v)1.1 mutation. Brain 136(12):3775–3786.  https://doi.org/10.1039/brain/awt300. PubMedPubMedCentralCrossRefGoogle Scholar
  29. Featherstone DE, Fujimoto E, Ruben PC (1998) A defect in sodium channel deactivation exacerbates hyperexcitability in human paramyotonia congenita. J Physiol 506(3):627–638PubMedPubMedCentralCrossRefGoogle Scholar
  30. Filatov GN, Pinter MJ, Rich MM (2005) Resting potential-dependent regulation of the voltage sensitivity of sodium channel gating in rat skeletal muscle in vivo. J Gen Physiol 126(2):161–172PubMedPubMedCentralCrossRefGoogle Scholar
  31. Francis DG, Rybalchencko V, Struyk AF, Cannon SC (2011) Leaky sodium channels from voltage sensor mutations in periodic paralysis, but not paramyotonia. Neurology 76(19):1635–1641.  https://doi.org/10.1212/WNL.0b013e318219fb57 PubMedPubMedCentralCrossRefGoogle Scholar
  32. Freites JA, Tobias DJ, White SH (2006) A voltage-sensor water pore. Biophys J 91:L90–L92PubMedPubMedCentralCrossRefGoogle Scholar
  33. Geukes Foppen RJ, van Mil HGJ, van Heukelom JS (2002) Effects of chloride transport on bistable behavior of the membrane potential in mouse skeletal muscle. J Physiol 542(1):181–191PubMedCrossRefGoogle Scholar
  34. Gosselin-Badaroudine P, Keller DI, Huang H, Pouliot V, Chatelier A, Osswald S, Brink M, Chahine M (2012a) A proton leak current through the cardiac sodium channel is linked to mixed arrhythmia and the dilated cardiomyopathy phenotype. PLoS One 7(5):e38331.  https://doi.org/10.1371/journal.pone.0038331 ADSPubMedPubMedCentralCrossRefGoogle Scholar
  35. Gosselin-Badaroudine P, Delemotte L, Moreau A, Klein ML, Chahine M (2012b) Gating pore currents and the resting state of rNav1.4 voltage sensor domains. Proc Natl Acad Sci U S A 109(47):19250–19255.  https://doi.org/10.1073/pnas.1217990 ADSPubMedPubMedCentralCrossRefGoogle Scholar
  36. Gosselin-Badaroudine P, Moreau A, Chahine M (2014) Nav1.5 mutations linked to dilated cardiomyopathy phenotypes. Is the gating pore current the missing link? Channels 8(1):90–94.  https://doi.org/10.4161/chan.27179. PubMedCrossRefGoogle Scholar
  37. Groome JR, Lehmann-Horn F, Fan C, Wolf M, Winston V, Merlini L, Jurkat-Rott K (2014) Nav1.4 mutations cause hypokalemic periodic paralysis by disrupting IIIS4 movement during recovery. Brain 137(4):998–1008.  https://doi.org/10.1093/brain/awu015 PubMedPubMedCentralCrossRefGoogle Scholar
  38. Guy HR, Seetharamulu P (1986) Molecular model of the action potential sodium channel. Proc Natl Acad Sci U S A 83(2):508–512ADSPubMedPubMedCentralCrossRefGoogle Scholar
  39. Hayward LJ, Brown RH, Cannon SC (1997) Slow inactivation differs among mutant Na channels associated with myotonia and periodic paralysis. Biophys J 72:1204–1219.  https://doi.org/10.1016/S0006-3495(97)78768-X PubMedPubMedCentralCrossRefGoogle Scholar
  40. Henrion U, Renhorn J, Borjesson SI, Neslon SI, Nelson EM, Schwaiger CS, Bjelkmar P, Wallner B, Lindhal E, Elinder F (2012) Tracking a complete voltage sensor with metal-ion bridges. Proc Natl Acad Sci U S A 109(22):8552–8557.  https://doi.org/10.1073/pnas.116938109. ADSPubMedPubMedCentralCrossRefGoogle Scholar
  41. Hershberger RE, Parks SB, Kushner JD, Li D, Ludwigsen S, Jakobs P, Nauman D, Burgess D, Partain J, Litt M (2008) Coding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP from 313 patients with familial or idiopathic dilated cardiomyopathy. Clin Transl Sci 1:21–26.  https://doi.org/10.1111/j.1752-8062.2008.00017.x PubMedPubMedCentralCrossRefGoogle Scholar
  42. Hodgkin AL, Huxley AF (1952) A quantitative description of membrane current and its application to conduction and excitation in nerve. J Physiol 117:500–544PubMedPubMedCentralCrossRefGoogle Scholar
  43. Holzherr BD, Groome JR, Fauler M, Nied E, Lehmann-Horn F, Jurkat-Rott K (2010) Characterization of a novel hNaV1.4 mutation causing hypokalemic periodic paralysis. Biophys Soc Pos-LB201Google Scholar
  44. Hong L, Pathak MM, Kim IH, Ta D, Tombola F (2013) Voltage-sensing domain of voltage-gated proton channel Hv1 shares mechanism of block with pore domains. Neuron 77:274–287.  https://doi.org/10.1016/j.neuron.2012.11.013 PubMedPubMedCentralCrossRefGoogle Scholar
  45. Jensen MO, Jogini V, Borhani DW, Leffler AE, Dror RO, Shaw DE (2012) Mechanism of voltage gating in potassium channels. Science 336(6078):229–233.  https://doi.org/10.1126/science.1216533 ADSPubMedCrossRefGoogle Scholar
  46. Jiang Y, Lee A, Ruta V, Cadene M, Chait BT, MacKinnon R (2003) X-ray structure of a voltage-dependent K+ channel. Nature 423(6935):33–41ADSPubMedCrossRefGoogle Scholar
  47. Jogini V, Roux B (2007) Dynamics of the Kv1.2 voltage-gated K+ channel in a membrane environment. Biophys J 93:3070–3082PubMedPubMedCentralCrossRefGoogle Scholar
  48. Jones DK, Ruben PC (2008) Biophysical defects in voltage-gated sodium channels associated with long QT and Brugada syndromes. Channels 2(2):70–80PubMedCrossRefGoogle Scholar
  49. Jurkat-Rott K, Lehmann-Horn F (2005) Muscle channelopathies and critical points in functional and genetic studies. J Clin Invest 115(8):2000–2009.  https://doi.org/10.1172/JCI25525 PubMedPubMedCentralCrossRefGoogle Scholar
  50. Jurkat-Rott K, Mitrovic N, Hang C, Kouzmekine A, Iaizzo P, Herzog J, Lerche H, Nicole S, Vale-Santos J, Chaveau D, Fontaine B, Lehmann-Horn F (2000) Voltage-sensor sodium channel mutations cause hypokalemic periodic paralysis type 2 by enhanced inactivation and reduced current. Proc Natl Acad Sci U S A 97(17):9549–9554ADSPubMedPubMedCentralCrossRefGoogle Scholar
  51. Jurkat-Rott K, Fauler M, Lehmann-Horn F (2006) Ion channels and ion transporters of the transverse tubular system of skeletal muscle. J Muscle Res Cell Motil 27(5-7):275–290PubMedCrossRefGoogle Scholar
  52. Jurkat-Rott K, Weber M-A, Fauler M, Guo X-H, Holzherr B, Paczulla A, Nordsborg N, Joechle W, Lehmann-Horn F (2009) K+-dependent paradoxical membrane depolarization and Na+ overload, major and reversible contributors to weakness by ion channel leaks. Proc Natl Acad Sci U S A 106(10):4036–4041.  https://doi.org/10.1073/pnas.0811277106 ADSPubMedPubMedCentralCrossRefGoogle Scholar
  53. Jurkat-Rott K, Holzherr B, Fauler M, Lehmann-Horn F (2010) Sodium channelopathies of skeletal muscle result from gain or loss of function. Pflugers Arch 460(2):239–248.  https://doi.org/10.1007/s00424-010-0814-4 PubMedPubMedCentralCrossRefGoogle Scholar
  54. Jurkat-Rott K, Groome J, Lehmann-Horn F (2012) Pathophysiological role of omega pore current in channelopathies. Front Pharmacol 3(112):1–19.  https://doi.org/10.3389/fphar.2012.00112. Google Scholar
  55. Kaminski GA, Friesner RA, Tirado-Rives J, Jorgensen WL (2001) Evaluation and reparametrization of the OPLS-AA force field for proteins via comparison with accurate quantum chemical calculations on peptides. J Phys Chem B 105:6474–6487.  https://doi.org/10.1021/jp003919d CrossRefGoogle Scholar
  56. Khalili-Araghi F, Jogini V, Yarov-Yarovoy V, Tajkhorshid E, Roux B, Schulten K (2010) Calculation of the gating charge for the Kv1.2 voltage activated potassium channel. Biophys J 98(10):2189–2198.  https://doi.org/10.1016/j.bpj.2010.02.056 PubMedPubMedCentralCrossRefGoogle Scholar
  57. Khalili-Araghi F, Tajkhorsid E, Roux B, Schulten K (2012) Molecular dynamics investigation of the ω-current in the Kv1.2 voltage sensor domains. Biophys J 102(2):258–267.  https://doi.org/10.1016/j.bpj.2011.10.057
  58. Kim M-K, Lee S-H, Park M-S, Kim B-C, Cho K-H, Lee M-C, Kim J-H, Kim S-M (2004) Mutation screening in Korean hypokalemic periodic paralysis: a novel SCN4A Arg672Cys mutation. Neuromuscul Disord 14(11):727–731PubMedCrossRefGoogle Scholar
  59. Krepkiy D, Mihailescu M, Freites JA, Schow EV, Worcester DL, Gawrisch K, Tobias DJ, White SH, Swartz KJ (2009) Structure and hydration of membranes embedded with voltage-sensing domains. Nature 462:473–479.  https://doi.org/10.1038/nature08542 ADSPubMedPubMedCentralCrossRefGoogle Scholar
  60. Kumanovics A, Levin G, Blount P (2002) Family ties of gating pores: evolution of the sensor module. FASEB J 16(12):1632–1639CrossRefGoogle Scholar
  61. Kuzmenkin A, Muncan V, Jurkat-Rott K, Hang C, Lerche H, Lehmann-Horn F, Mitrovic N (2002) Enhanced inactivation and pH sensitivity of Na(+) channel mutations causing hypokalemic periodic paralysis type II. Brain 125(4):835–843PubMedCrossRefGoogle Scholar
  62. Larsson HP, Baker OS, Dhillon DS, Isacoff EY (1996) Transmembrane movement of the Shaker K+ channel S4. Neuron 16:387–397PubMedCrossRefGoogle Scholar
  63. Laurent G, Saal S, Amarouch MY, Beziau DM, Marsman RFJ, Faivre L, Barc J, Dina C, Bertaux G, Barthez O, Thauvin-Roubinet C, Charron P, Fressart V, Maltret A, Villain E, Baron E, Merot J, Turpault R, Coudiere Y, Charpentier F, Schott J-J, Loussouarn G, Wilde AAM, Wolf J-E, Baro I, Kyndt F, Probst V (2012) Multifocal ectopic Purkinje-related premature contractions: a new SCN5A-related cardiac channelopathy. J Am Coll Cardiol 60:144–156.  https://doi.org/10.1016/j.jacc.2012.02.052. PubMedCrossRefGoogle Scholar
  64. Leach AR (2001) Molecular modeling – principles and applications, 2nd edn. Pearson Education, HarlowGoogle Scholar
  65. Lehmann-Horn F, Jurkat-Rott K (1999) Voltage-gated ion channels and hereditary disease. Physiol Rev 79(4):1317–1372PubMedGoogle Scholar
  66. Lehmann-Horn F, Rudel R, Jurkat-Rott K (2004) Non-dystrophic myotonias and periodic paralyses. In: Engel AG, Franzini-Armstrong C (eds) Myology, 3rd edn. McGraw-Hill, New York, pp 1257–1300Google Scholar
  67. Li Q, Wanderling S, Paduch M, Medovoy D, Singharoy A, McGeevy R, Villalba-Galea C, Hulse RE, Roux B, Schulten K, Kossiakoff A, Perozo E (2014) Structural mechanism of voltage-dependent gating in an isolated voltage-sensing domain. Nat Struct Mol Biol 21(3):244–252.  https://doi.org/10.1038/nsmb.2768 PubMedPubMedCentralCrossRefGoogle Scholar
  68. Lin S-H, Huang C-L (2012) Mechanism of thyrotoxic periodic paralysis. J Am Soc Nehprhol 23(6):985–988.  https://doi.org/10.1681/ASN.2012010046 Google Scholar
  69. Lin M-C, Abramson J, Papazian DM (2010) Transfer of ion binding site from ether-a-go-go to Shaker: Mg2+ binds to resting state to modulate channel opening. J Gen Physiol 135(5):415–431.  https://doi.org/10.1085/jgp.200910320 PubMedPubMedCentralCrossRefGoogle Scholar
  70. Loussouarn G, Sternberg D, Nicole S, Marionneau C, Bouffant FL, Toumaniantz G, Barc J, Malak OA, Fressart V, Pereon Y, Baro I, Charpentier F (2016) Physiological and pathophysiological insights of Nav1.4 and Nav1.5 comparison. Front Pharmacol 6(314):1–20.  https://doi.org/10.3389/fphar.2015.00314. Google Scholar
  71. MacKerell AD, Brooks B, Brooks CL, Nilsson L, Roux B, Won Y, Karplus M (2002) CHARMM: the energy function and its parameterization. In: Encyclopedia of computational chemistry. Wiley, ChichesterGoogle Scholar
  72. Mankodi A, Grunseich C, Skov M, Cook L, Aue G, Purev E, Bakar D, Lehky T, Jurkat-Rott K, Pedersen TH, Childs RW (2015) Divalent cation-responsive myotonia and muscle paralysis in skeletal muscle channelopathy. Neuromuscul Disord 25(11):908–912.  https://doi.org/10.1016/j.nmd.2015.08.007 PubMedPubMedCentralCrossRefGoogle Scholar
  73. Mann SA, Castro ML, Ohanian M, Guo G, Zodgekar P, Sheu A, Stockhammer K, Thompson T, Playford D, Subbiah R, Kuchar D, Aggarwal A, Vandenberg JI, Fatkin D (2012) R222Q SCN5A mutation is associated with reversible ventricular ectopy and dilated cardiomyopathy. J Am Coll Cardiol 60(16):1566–1573.  https://doi.org/10.1016/j.jacc.2012.05.050 PubMedCrossRefGoogle Scholar
  74. Matthews E, Labrum R, Sweeney MG, Sud R, Haworth A, Chinnery PF, Meola G, Schorge S, Kullman DM, Davis MB, Hanna MG (2009) Voltage sensor loss accounts for most cases of hypokalemic periodic paralysis. Neurology 72:1544–1547.  https://doi.org/10.1212/01.wnl.0000342387.65477.46. PubMedPubMedCentralCrossRefGoogle Scholar
  75. Matthews E, Fialho D, Tan SV, Venance SL, Cannon SC, Sternberg D, Fontaine B, Amato AA, Barohn RJ, Griggs RC, Hanna MG (2010) The non-dystrophic myotonias: molecular pathogenesis, diagnosis and treatment. Brain 133(1):9–22.  https://doi.org/10.1093/brain/awp294 PubMedCrossRefGoogle Scholar
  76. Matthews E, Portaro S, Ke Q, Sud R, Haworth A, Davis MB, Griggs RC, Hanna MG (2011) Acetazolamide efficacy in hypokalemic periodic paralysis and the predictive role of genotype. Neurology 77(22):1960–1964.  https://doi.org/10.1212/WNL.0b013e31823a0cb6 PubMedPubMedCentralCrossRefGoogle Scholar
  77. McNair WP, Sinagra G, Taylor MRG, Lenarda AD, Ferguso DA, Salcedo EF, Slavov D, Zhu X, Caldwell JH, Mestroni L (2011) SCN5A mutations associate with arrhythmic dilated cardiomyopathy and commonly localize to the voltage sensing mechanism. J Am Coll Cardiol 57(21):2160–2168.  https://doi.org/10.1016/jacc.2010.09.084. PubMedCrossRefGoogle Scholar
  78. Mi W, Rybalchenko V, Cannon SC (2014) Disrupted coupling of gating charge displacement to Na+ current activation for DIIS4 mutations in hypokalemic periodic paralysis. J Gen Physiol 144(2):137–145.  https://doi.org/10.1085/jgp.201411199 PubMedPubMedCentralCrossRefGoogle Scholar
  79. Moreau A, Chahine M (2015) Omega pore, and alternative ion channel permeation pathway involved in the development of several channelopathies. Med Sci 31(8–9):735–741.  https://doi.org/10.1051/medsci/20153108011. Google Scholar
  80. Moreau A, Gosselin-Badaroudine P, Chahine M (2014) Biophysics, pathophysiology, and pharmacology of ion channel gating pores. Front Pharmacol 5(53):1–19.  https://doi.org/10.3389/fphar.2014.00053. Google Scholar
  81. Moreau A, Gosselin-Badaroudine P, Delemotte L, Klein ML, Chahine M (2015a) Gating pore currents are defects in common with two Nav1.5 patients with mixed arrythmias and dilated cardiomyopathy. J Gen Physiol 145(2):93–106.  https://doi.org/10.1085/jgp.201411304 PubMedPubMedCentralCrossRefGoogle Scholar
  82. Moreau A, Gosselin-Badaroudine P, Boutjdir M, Chahine M (2015b) Mutations in the voltage sensors of domains I and II of Nav1.5 that are associated with arrhythmias and dilated cardiomyopathy generate gating pore currents. Front Pharmacol 6(301):1–12.  https://doi.org/10.3389/fphar.2015.00301. Google Scholar
  83. Morrill JA, Brown RH Jr, Cannon SC (1998) Gating of the L-type Ca channel in human skeletal myotubes: an activation defect caused by hypokalemic periodic paralysis mutation R528H. J Neurosci 18(24):10320–10334PubMedGoogle Scholar
  84. Nagel AM, Lehmann-Horn F, Weber M-A, Jurkat-Rott K, Wolf MB, Radbruch A, Umathum R, Semmler W (2014) In vivo 35Cl MR imaging in humans: a feasibility study. Radiology 271(2):585–595.  https://doi.org/10.1148/radiol.1313151617 PubMedCrossRefGoogle Scholar
  85. Nair K, Pekhletski R, Harris L, Care M, Morel C, Farid T, Backx PH, Szabo E, Nanthakumar K (2012) Escape capture bigeminy: phenotypic marker of cardiac soidum channel voltage sensor mutation R222Q. Heart Rhythm 9:1681–1688.  https://doi.org/10.1016/j.hrthm.2012.06.029 PubMedCrossRefGoogle Scholar
  86. Nguyen TP, Wang DW, Rhodes TH, George AL Jr (2008) Divergent biophysical defects caused by mutant sodium channels in dilated cardiomyopathy with arrhythmia. Circ Res 102(3):364–371.  https://doi.org/10.1161/CIRCRESAHA.107.164673 PubMedCrossRefGoogle Scholar
  87. Noda MS, Shizimu S, Tanabe T, Takai T, Kayano T, Ikeda T, Takahashi H, Nakayami Y, Kamaoka N, Minamino N, Kangawa K, Matsuo K, Raferty H, Hirose M, Inayama T, Hayashida H, Miyata T, Numa S (1984) Primary structure of Electrophorus electricus sodium channel deduced from cDNA sequence. Nature 312:121–127ADSPubMedCrossRefGoogle Scholar
  88. Olson TM, Michels VV, Ballew JD, Reyna SP, Karst ML, Herron KJ, Horton SC, Rodeheffer RJ, Anderson JL (2005) Sodium channel mutations and susceptibility to heart failure and atrial fibrillation. JAMA 293(4):447–454.  https://doi.org/10.1001/jama.293.4.447 PubMedPubMedCentralCrossRefGoogle Scholar
  89. Payandeh J, El-Din G, Scheuer T, Zheng N, Catterall WA (2012) Crystal structure of a voltage-gated sodium channel in two potentially inactivated states. Nature 486(7401):135–140.  https://doi.org/10.1038/nature10238 ADSPubMedPubMedCentralGoogle Scholar
  90. Plaster NM, Tawil R, Tristani-Firouzi M, Canun S, Bendahhou S, Tsunoda A, Donaldson MR, Iannaccone ST, Brunt E, Barohn R, Clark J, Deymeer F, George AL Jr, Fish FA, Hahn A, Nitu A, Ozdemir C, Serdaroglu P, Subramony SH, Wolfe G, Fu Y-H, Ptacek LJ (2001) Mutations in Kir2.1 cause the development and episodic electrical phenotypes of Anderson’s syndrome. Cell 105(4):511–519PubMedCrossRefGoogle Scholar
  91. Platt D, Griggs R (2009) Skeletal muscle channelopathies: new insights into the periodic paralyses and non-dystrophic myotonias. Curr Opin Neurol 22(5):524–531.  https://doi.org/10.1097/WCO.0b013e32832efa9f. PubMedPubMedCentralCrossRefGoogle Scholar
  92. Posson DJ, Ge P, Miller C, Bezanilla F, Selvin PR (2005) Small vertical movement of a K+ voltage-sensor measured with luminescence energy transfer. Nature 436(7052):848–851.  https://doi.org/10.1038/nature03819 ADSPubMedPubMedCentralCrossRefGoogle Scholar
  93. Richmond JE, VanDeCarr D, Featherstone DE, George AL Jr, Ruben PC (1997) Defective fast inactivation recovery and deactivation account for sodium channel myotonia in the I1160V mutant. Biophys J 73(4):1896–1903PubMedPubMedCentralCrossRefGoogle Scholar
  94. Ruff RL (2000) Skeletal muscle sodium current is reduced in hypokalemic periodic paralysis. Proc Natl Acad Sci U S A 97(18):9832–9833ADSPubMedPubMedCentralCrossRefGoogle Scholar
  95. Ryan DP, da Silva MRD, Soong TW, Fontaine B, Donaldson MR, Kung AWC, Jongjaroenprasert W, Liang MC, Khoo DHC, Cheah JS, Ho SC, Bernstein HS, Macie RMB, Brown RH Jr, Ptacek LJ (2010) Mutations in potassium channel Kir2.6 cause susceptibility to thyrotoxic hypokalemic periodic paralysis. Cell 140(1):88–98.  https://doi.org/10.1016/j.cell2009.12.024 PubMedPubMedCentralCrossRefGoogle Scholar
  96. Sansone V, Meola G, Links TP, Panzeri M, Rose MR (2008) Treatment for periodic paralysis. Cochrane Database Syst Rev 1:CD005045.  https://doi.org/10.1002/14651858.CD005045.pub2 Google Scholar
  97. Sansone VA, Burge J, McDermott MP, Smith PC, Herr B, Tawil R, Pandya S, Kissel J, Ciafaioni E, Shieh P, Ralph JW, Amato A, Cannon SC, Trivedi J, Barohn R, Crum B, Misumoto H, Pestronk A, Meola G, Griggs R (2016) Randomized, placebo-controlled trials of dichlorophenamide in periodic paralysis. Neurology 86(15):1408–1416.  https://doi.org/10.1212/WNL.0000000000002416 PubMedPubMedCentralCrossRefGoogle Scholar
  98. Schwaiger CS, Börjesson SI, Hess B, Wallner B, Elinder F, Lindahl E (2012) The free energy barrier for arginine gating charge translation is altered by mutations in the voltage sensor domain. PLoS One 7:e45880.  https://doi.org/10.1371/journal.pone.0045880 ADSPubMedPubMedCentralCrossRefGoogle Scholar
  99. Shen H, Zhou Q, Pan X, Li Z, Wu J, Yan N (2017) Structure of a eukaryotic voltage-gated sodium channel at near-atomic resolution. Science 355:eaal4326.  https://doi.org/10.1126/science.aal4326 PubMedCrossRefGoogle Scholar
  100. Sokolov S, Scheuer T, Catterall WA (2007) Gating pore currents in an inherited channelopathy. Nature 446(7131):76–78ADSPubMedCrossRefGoogle Scholar
  101. Sokolov S, Scheuer T, Catterall WA (2008) Depolarization-activated gating pore current conducted by mutant sodium channels in potassium-sensitive normokalemic periodic paralysis. Proc Natl Acad Sci U S A 105(50):19980–19985.  https://doi.org/10.1073/pnas.0810562105 ADSPubMedPubMedCentralCrossRefGoogle Scholar
  102. Sokolov S, Scheuer T, Catterall WA (2010) Ion permeation and block of the gating pore in the voltage sensor of Nav1.4 channels with hypokalemic periodic paralysis mutations. J Gen Physiol 136(2):225–236.  https://doi.org/10.1085/jgp.201010414 PubMedPubMedCentralCrossRefGoogle Scholar
  103. Song Y-W, Kim S-J, Heo T-H, Kim M-H, Kim J-B (2012) Normokalemic periodic paralysis is not a distinct disease. Muscle Nerve 46(6):914–916. https://doi.org/10.1002/mus.23441
  104. Starace DM, Bezanilla F (2004) A proton pore in a potassium channel voltage sensor reveals a focused electric field. Nature 427(6974):548–553ADSPubMedCrossRefGoogle Scholar
  105. Sternberg D, Maisonobe T, Jurkat-Rott K, Nicole S, Launay E, Chauveau D, Tabti N, Lehmann-Horn F, Hainque B, Fontaine B (2001) Hypokalemic periodic paralysis type 2 caused by mutations at codon 672 in the muscle sodium channel gene SCN4A. Brain 124(6):1091–1099PubMedCrossRefGoogle Scholar
  106. Struyk AF, Cannon SC (2007) A Na+ channel mutation linked to hypokalemic periodic paralysis exposes a proton-selective gating pore. J Gen Physiol 130(1):11–20PubMedPubMedCentralCrossRefGoogle Scholar
  107. Struyk AF, Cannon SC (2008) Paradoxical depolarization of Ba2+ treated muscle exposed to low extracellular K+: insights into resting potential abnormalities in hypokalemic periodic paralysis. Muscle Nerve 37(3):326–337PubMedCrossRefGoogle Scholar
  108. Struyk AF, Scoggan KA, Bulman DE, Cannon SC (2000) The human skeletal muscle Na channel mutation R669H associated with hypokalemic periodic paralysis enhances slow inactivation. J Neurosci 20(23):8010–8017Google Scholar
  109. Struyk AF, Markin VS, Francis D, Cannon SC (2008) Gating pore currents in DIIS4 mutations of Nav1.4 associated with periodic paralysis: saturation of ion flux and implications of disease pathogenesis. J Gen Physiol 132(4):447–464.  https://doi.org/10.1085/jgp.200809967 PubMedPubMedCentralCrossRefGoogle Scholar
  110. Stuhmer W, Conti F, Suzuki H, Wang X, Noda N, Yahagi N, Kubo H, Numa S (1989) Structural parts involved in activation and inactivation of the sodium channel. Nature 339(6226):597–603ADSPubMedCrossRefGoogle Scholar
  111. Sugiura Y, Makita N, Li L, Noble PJ, Kimura J, Kumagai Y, Soeda T, Yamamoto T (2003) Cold induces shifts of voltage dependence in mutant SCN4A, causing hypokalemic periodic paralysis. Neurology 61(7):914–918PubMedCrossRefGoogle Scholar
  112. Tao X, Lee A, Limapichat W, Dougherty DA, MacKinnon R (2010) A gating charge transfer center in voltage sensors. Science 328:67–73.  https://doi.org/10.1126/science.1185954 ADSPubMedPubMedCentralCrossRefGoogle Scholar
  113. Tombola F, Pathak MM, Isacoff EY (2005) Voltage-sensing arginines in a potassium channel permeate and occlude cation-selective pores. Neuron 45(3):379–388PubMedCrossRefGoogle Scholar
  114. Tombola F, Pathak MM, Gorostiza P, Isacoff EY (2006) The twisted ion-permeation pathway of a resting voltage-sensing domain. Nature 445:546–549.  https://doi.org/10.1038/nature05396 PubMedCrossRefGoogle Scholar
  115. Treptow W, Tarek M (2006) Environment of the gating charges in the Kv1.2 Shaker potassium channel. Biophys J 90:L64–L66PubMedPubMedCentralCrossRefGoogle Scholar
  116. Tricarico D, Camerino DC (2011) Recent advances in the pathogenesis and drug action in periodic paralysis and related channelopathies. Front Pharmacol 2(8):1–8.  https://doi.org/10.3389/fphar.2011.00008. Google Scholar
  117. Tricarico D, Barbieri M, Mele A, Carbonara G, Camerino DC (2004) Carbonic anhydrase inhibitors are specific openers of skeletal muscle BK channel of K+ deficient rats. FASEB J 18(6):760–761PubMedGoogle Scholar
  118. Tricarico D, Mele A, Camerino DC (2006) Carbonic anhydrase inhibitors ameliorate the symptoms of hypokalemic periodic paralysis in rats by opening the muscular Ca2+-activated-K+ channels. Neuromuscul Disord 16(1):39–45PubMedCrossRefGoogle Scholar
  119. Tricarico D, Lovaglio S, Mele A, Rotondo G, Mancinelli E, Meola G, Camerino DC (2008) Acetazolamide prevents vacuolar myopathy in skeletal muscle K(+)-depleted rats. Br J Pharmacol 154(1):183–190.  https://doi.org/10.1038/bjp.2008.42 PubMedPubMedCentralCrossRefGoogle Scholar
  120. Tristani-Firouzi M, Etheridge SP (2010) Kir2.1 channelopathies: the Anderson-Tawil syndrome. Pflugers Arch 460(2):289–294.  https://doi.org/10.1007/s00424-010-0820-6 PubMedCrossRefGoogle Scholar
  121. Vargas E, Yarov-Yarovoy V, Khalili-Araghi F, Catterall WA, Klein ML, Tarek M, Lindhal E, Schulten K, Perozo E, Bezanilla F, Roux B (2012) An emerging consensus on voltage-dependent gating from computational modeling and molecular dynamics simulations. J Gen Physiol 140(6):587–594.  https://doi.org/10.1085/jgp.201210873 PubMedPubMedCentralCrossRefGoogle Scholar
  122. Venance SL, Cannon SC, Fialho D, Fontaine B, Hanna MG, Ptacek LJ, Tristani-Fiorouzi M, Tawil R, Griggs RC (2006) The primary periodic paralyses: diagnosis, pathogenesis and treatment. Brain 129(1):8–17PubMedCrossRefGoogle Scholar
  123. Vicart S, Sternberg D, Fournier E, Ochsner F, Laforet P, Kuntzer T, Eymard B, Hainque B, Fontaine B (2004) New mutations at SCN4A cause a potassium-sensitive normokalemic periodic paralysis. Neurology 63(11):2120–2127PubMedCrossRefGoogle Scholar
  124. Vicart S, Sternberg D, Fontaine B, Meola G (2005) Human skeletal muscle sodium channelopathies. Neurol Sci 26(4):194–202PubMedCrossRefGoogle Scholar
  125. Wang J, Wang W, Kollman PA, Case DA (2006) Automatic atom type and bond type perception in molecular mechanical calculations. J Mol Graph Model 25:247–260.  https://doi.org/10.1016/j.jmgm.2005.12.005 ADSPubMedCrossRefGoogle Scholar
  126. Webb J, Cannon SC (2008) Cold-induced defects of sodium channel gating in atypical periodic paralysis plus myotonia. Neurology 70(10):755–761PubMedCrossRefGoogle Scholar
  127. Weber MA, Nagel AM, Marschar AM, Glemser P, Jurkat-Rott K, Wolf MB, Ladd ME, Schlemmer HP, Kauczor HU, Lehmann-Horn F (2016) 7-T (35)Cl and (23)Na MR imaging for detection of mutation-dependent alterations in muscular edema and fat fraction with sodium and chloride concentrations in periodic paralysis. Radiology 280(3):848–859.  https://doi.org/10.1148/radiol.2016151617 PubMedCrossRefGoogle Scholar
  128. Wood ML, Freites JA, Tombola F, Tobias DJ (2017) Atomistic modeling of ion conduction through the voltage-sensing domain of the Shaker K+ ion channel. J Phys Chem B 121:3804–3812.  https://doi.org/10.1021/acs.jpcb.6b12639 PubMedCrossRefGoogle Scholar
  129. Wu F, Cannon SC (2017) Stac3 facilitated expression of Cav1.1 in Xenopus oocytes to assess functional consequences of HypoPP mutant Cav1.1-R528H. Biophys Abstr 112(3):245aADSGoogle Scholar
  130. Wu F, Mi W, Burns DK, Fu Y, Gray HF, Struyk AF, Cannon SC (2011) A sodium channel knockin mutant (Nav1.4-R669H) mouse model of hypokalemic periodic paralysis. J Clin Invest 121(10):4082–4094.  https://doi.org/10.1172/JCI57398 PubMedPubMedCentralCrossRefGoogle Scholar
  131. Wu F, Mi W, Cannon SC (2013a) Bumetanide prevents transient decreases in muscle force in murine hypokalemic periodic paralysis. Neurology 80(12):1110–1116.  https://doi.org/10.1212/WNL.0b013e3182886a0e PubMedPubMedCentralCrossRefGoogle Scholar
  132. Wu F, Mi W, Cannon SC (2013b) Beneficial effects of bumetamide in a Cav1.1-R528H mouse model of hypokalemic periodic paralysis. Brain 136(12):3766–3774.  https://doi.org/10.1093/brain/awt280 PubMedPubMedCentralCrossRefGoogle Scholar
  133. Yang N, Horn R (1995) Evidence for voltage-dependent S4 movement in sodium channels. Neuron 15(1):213–218PubMedCrossRefGoogle Scholar
  134. Yang N, George AL Jr, Horn R (1996) Molecular basis of charge movement in voltage-gated sodium channels. Neuron 16(1):113–122PubMedCrossRefGoogle Scholar
  135. Yu FH, Catterall WA (2004) The VGL-chanome: a protein superfamily specialized for electrical signaling and ionic homeostasis. Sci STKE 2004:re15.  https://doi.org/10.1126/stke.2532004re15 PubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of Biological SciencesIdaho State UniversityPocatelloUSA
  2. 2.Institut NeuroMyogene, ENS de Lyon, Site MONODLyonFrance
  3. 3.Science for Life Laboratory, Department of PhysicsKTH Royal Institute of TechnologySolnaSweden

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