Regulation of Cardiac Voltage-Gated Sodium Channel by Kinases: Roles of Protein Kinases A and C

  • Ademuyiwa S. Aromolaran
  • Mohamed Chahine
  • Mohamed BoutjdirEmail author
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 246)


In the heart, voltage-gated sodium (Nav) channel (Nav1.5) is defined by its pore-forming α-subunit and its auxiliary β-subunits, both of which are important for its critical contribution to the initiation and maintenance of the cardiac action potential (AP) that underlie normal heart rhythm. The physiological relevance of Nav1.5 is further marked by the fact that inherited or congenital mutations in Nav1.5 channel gene SCN5A lead to altered functional expression (including expression, trafficking, and current density), and are generally manifested in the form of distinct cardiac arrhythmic events, epilepsy, neuropathic pain, migraine, and neuromuscular disorders. However, despite significant advances in defining the pathophysiology of Nav1.5, the molecular mechanisms that underlie its regulation and contribution to cardiac disorders are poorly understood. It is rapidly becoming evident that the functional expression (localization, trafficking and gating) of Nav1.5 may be under modulation by post-translational modifications that are associated with phosphorylation. We review here the molecular basis of cardiac Na channel regulation by kinases (PKA and PKC) and the resulting functional consequences. Specifically, we discuss: (1) recent literature on the structural, molecular, and functional properties of cardiac Nav1.5 channels; (2) how these properties may be altered by phosphorylation in disease states underlain by congenital mutations in Nav1.5 channel and/or subunits such as long QT and Brugada syndromes. Our expectation is that understanding the roles of these distinct and complex phosphorylation processes on the functional expression of Nav1.5 is likely to provide crucial mechanistic insights into Na channel associated arrhythmogenic events and will facilitate the development of novel therapeutic strategies.


Brugada syndrome Long QT syndrome 3 Protein kinase A Protein kinase C Voltage-gated sodium channel 


  1. Abriel H, Kass RS (2005) Regulation of the voltage-gated cardiac sodium channel Nav1.5 by interacting proteins. Trends Cardiovasc Med 15:35–40PubMedCrossRefGoogle Scholar
  2. Abriel H, Rougier JS, Jalife J (2015) Ion channel macromolecular complexes in cardiomyocytes: roles in sudden cardiac death. Circ Res 116:1971–1988PubMedPubMedCentralCrossRefGoogle Scholar
  3. Aiba T, Farinelli F, Kostecki G, Hesketh GG, Edwards D, Biswas S, Tung L, Tomaselli GF (2014) A mutation causing Brugada syndrome identifies a mechanism for altered autonomic and oxidant regulation of cardiac sodium currents. Circ Cardiovasc Genet 7:249–256PubMedPubMedCentralCrossRefGoogle Scholar
  4. Amin AS, Verkerk AO, Bhuiyan ZA, Wilde AA, Tan HL (2005) Novel Brugada syndrome-causing mutation in ion-conducting pore of cardiac Na+ channel does not affect ion selectivity properties. Acta Physiol Scand 185:291–301PubMedCrossRefGoogle Scholar
  5. Amin AS, Pinto YM, Wilde AA (2013) Long QT syndrome: beyond the causal mutation. J Physiol 591:4125–4139PubMedPubMedCentralCrossRefGoogle Scholar
  6. Baba S, Dun W, Boyden PA (2004) Can PKA activators rescue Na+ channel function in epicardial border zone cells that survive in the infarcted canine heart? Cardiovasc Res 64:260–267PubMedCrossRefGoogle Scholar
  7. Bennett PB, Yazawa K, Makita N, George AL Jr (1995) Molecular mechanism for an inherited cardiac arrhythmia. Nature 376:683–685PubMedPubMedCentralCrossRefGoogle Scholar
  8. Boutjdir M, Restivo M, Wei Y, Stergiopoulos K, el-Sherif N (1994) Early afterdepolarization formation in cardiac myocytes: analysis of phase plane patterns, action potential, and membrane currents. J Cardiovasc Electrophysiol 5:609–620PubMedCrossRefGoogle Scholar
  9. Bradbury NA, Bridges RJ (1994) Role of membrane trafficking in plasma membrane solute transport. Am J Phys 267:C1–24CrossRefGoogle Scholar
  10. Chadda KR, Jeevaratnam K, Lei M, Huang CL (2017) Sodium channel biophysics, late sodium current and genetic arrhythmic syndromes. Pflugers Arch 469:629–641PubMedPubMedCentralCrossRefGoogle Scholar
  11. Chahine M, O’Leary ME (2014) Regulation/modulation of sensory neuron sodium channels. Handb Exp Pharmacol 221:111–135PubMedPubMedCentralCrossRefGoogle Scholar
  12. Chandra R, Chauhan VS, Starmer CF, Grant AO (1999) Beta-adrenergic action on wild-type and KPQ mutant human cardiac Na+ channels: shift in gating but no change in Ca2+:Na+ selectivity. Cardiovasc Res 42:490–502PubMedCrossRefGoogle Scholar
  13. Chen J, Makiyama T, Wuriyanghai Y, Ohno S, Sasaki K, Hayano M, Harita T, Nishiuchi S, Yuta Y, Ueyama T, Shimizu A, Horie M, Kimura T (2016) Cardiac sodium channel mutation associated with epinephrine-induced QT prolongation and sinus node dysfunction. Heart Rhythm 13:289–298PubMedCrossRefGoogle Scholar
  14. Chen-Izu Y, Shaw RM, Pitt GS, Yarov-Yarovoy V, Sack JT, Abriel H, Aldrich RW, Belardinelli L, Cannell MB, Catterall WA, Chazin WJ, Chiamvimonvat N, Deschenes I, Grandi E, Hund TJ, Izu LT, Maier LS, Maltsev VA, Marionneau C, Mohler PJ, Rajamani S, Rasmusson RL, Sobie EA, Clancy CE, Bers DM (2015) Na+ channel function, regulation, structure, trafficking and sequestration. J Physiol 593:1347–1360PubMedPubMedCentralCrossRefGoogle Scholar
  15. Chinushi M, Tagawa M, Sugiura H, Komura S, Hosaka Y, Washizuka T, Aizawa Y (2003) Ventricular tachyarrhythmias in a canine model of LQT3: arrhythmogenic effects of sympathetic activity and therapeutic effects of mexiletine. Circ J 67:263–268PubMedCrossRefGoogle Scholar
  16. Clancy CE, Rudy Y (1999) Linking a genetic defect to its cellular phenotype in a cardiac arrhythmia. Nature 400:566–569PubMedCrossRefGoogle Scholar
  17. Clancy CE, Tateyama M, Kass RS (2002) Insights into the molecular mechanisms of bradycardia-triggered arrhythmias in long QT-3 syndrome. J Clin Invest 110:1251–1262PubMedPubMedCentralCrossRefGoogle Scholar
  18. Clancy CE, Kurokawa J, Tateyama M, Wehrens XH, Kass RS (2003) K+ channel structure-activity relationships and mechanisms of drug-induced QT prolongation. Annu Rev Pharmacol Toxicol 43:441–461PubMedCrossRefGoogle Scholar
  19. Crotti L, Celano G, Dagradi F, Schwartz PJ (2008) Congenital long QT syndrome. Orphanet J Rare Dis 3:18PubMedPubMedCentralCrossRefGoogle Scholar
  20. Crotti L, Marcou CA, Tester DJ, Castelletti S, Giudicessi JR, Torchio M, Medeiros-Domingo A, Simone S, Will ML, Dagradi F, Schwartz PJ, Ackerman MJ (2012) Spectrum and prevalence of mutations involving BrS1- through BrS12-susceptibility genes in a cohort of unrelated patients referred for Brugada syndrome genetic testing: implications for genetic testing. J Am Coll Cardiol 60:1410–1418PubMedPubMedCentralCrossRefGoogle Scholar
  21. Cusdin FS, Clare JJ, Jackson AP (2008) Trafficking and cellular distribution of voltage-gated sodium channels. Traffic 9:17–26PubMedCrossRefGoogle Scholar
  22. Dai S, Hall DD, Hell JW (2009) Supramolecular assemblies and localized regulation of voltage-gated ion channels. Physiol Rev 89:411–452PubMedPubMedCentralCrossRefGoogle Scholar
  23. Dascal N, Lotan I (1991) Activation of protein kinase C alters voltage dependence of a Na+ channel. Neuron 6:165–175PubMedCrossRefGoogle Scholar
  24. Dhar Malhotra J, Chen C, Rivolta I, Abriel H, Malhotra R, Mattei LN, Brosius FC, Kass RS, Isom LL (2001) Characterization of sodium channel alpha- and beta-subunits in rat and mouse cardiac myocytes. Circulation 103:1303–1310PubMedPubMedCentralCrossRefGoogle Scholar
  25. Dorn GW 2nd, Souroujon MC, Liron T, Chen CH, Gray MO, Zhou HZ, Csukai M, Wu G, Lorenz JN, Mochly-Rosen D (1999) Sustained in vivo cardiac protection by a rationally designed peptide that causes epsilon protein kinase C translocation. Proc Natl Acad Sci U S A 96:12798–12803PubMedPubMedCentralCrossRefGoogle Scholar
  26. Dulsat G, Palomeras S, Cortada E, Riuro H, Brugada R, Verges M (2017) Trafficking and localization to the plasma membrane of Nav1.5 promoted by the beta2 subunit is defective due to a beta2 mutation associated with Brugada syndrome. Biol Cell 109:273–291PubMedPubMedCentralCrossRefGoogle Scholar
  27. el-Sherif N, Fozzard HA, Hanck DA (1992) Dose-dependent modulation of the cardiac sodium channel by sea anemone toxin ATXII. Circ Res 70:285–301PubMedCrossRefGoogle Scholar
  28. Fahmi AI, Patel M, Stevens EB, Fowden AL, John JE 3rd, Lee K, Pinnock R, Morgan K, Jackson AP, Vandenberg JI (2001) The sodium channel beta-subunit SCN3b modulates the kinetics of SCN5a and is expressed heterogeneously in sheep heart. J Physiol 537:693–700PubMedPubMedCentralCrossRefGoogle Scholar
  29. Ferreira JC, Brum PC, Mochly-Rosen D (2011) BetaIIPKC and epsilonPKC isozymes as potential pharmacological targets in cardiac hypertrophy and heart failure. J Mol Cell Cardiol 51:479–484PubMedCrossRefGoogle Scholar
  30. Ferreira JC, Mochly-Rosen D, Boutjdir M (2012) Regulation of cardiac excitability by protein kinase C isozymes. Front Biosci (Schol Ed) 4:532–546CrossRefGoogle Scholar
  31. Frohnwieser B, Chen LQ, Schreibmayer W, Kallen RG (1997) Modulation of the human cardiac sodium channel alpha-subunit by cAMP-dependent protein kinase and the responsible sequence domain. J Physiol 498(2):309–318PubMedPubMedCentralCrossRefGoogle Scholar
  32. Fu Q, Xiang YK (2015) Trafficking of beta-adrenergic receptors: implications in intracellular receptor signaling. Prog Mol Biol Transl Sci 132:151–188PubMedCrossRefGoogle Scholar
  33. Gawali VS, Todt H (2016) Mechanism of inactivation in voltage-gated Na(+) channels. Curr Top Membr 78:409–450PubMedCrossRefGoogle Scholar
  34. Gintant GA, Liu DW (1992) Beta-adrenergic modulation of fast inward sodium current in canine myocardium. Syncytial preparations versus isolated myocytes. Circ Res 70(4):844–850PubMedCrossRefGoogle Scholar
  35. Grant AO (2001) Molecular biology of sodium channels and their role in cardiac arrhythmias. Am J Med 110:296–305PubMedCrossRefGoogle Scholar
  36. Hallaq H, Yang Z, Viswanathan PC, Fukuda K, Shen W, Wang DW, Wells KS, Zhou J, Yi J, Murray KT (2006) Quantitation of protein kinase A-mediated trafficking of cardiac sodium channels in living cells. Cardiovasc Res 72:250–261PubMedPubMedCentralCrossRefGoogle Scholar
  37. Hallaq H, Wang DW, Kunic JD, George AL Jr, Wells KS, Murray KT (2012) Activation of protein kinase C alters the intracellular distribution and mobility of cardiac Na+ channels. Am J Physiol Heart Circ Physiol 302:H782–H789CrossRefPubMedPubMedCentralGoogle Scholar
  38. Hu D, Barajas-Martinez H, Medeiros-Domingo A, Crotti L, Veltmann C, Schimpf R, Urrutia J, Alday A, Casis O, Pfeiffer R, Burashnikov E, Caceres G, Tester DJ, Wolpert C, Borggrefe M, Schwartz P, Ackerman MJ, Antzelevitch C (2012) A novel rare variant in SCN1Bb linked to Brugada syndrome and SIDS by combined modulation of Na(v)1.5 and K(v)4.3 channel currents. Heart Rhythm 9:760–769PubMedPubMedCentralCrossRefGoogle Scholar
  39. Ishibashi K, Aiba T, Kamiya C, Miyazaki A, Sakaguchi H, Wada M, Nakajima I, Miyamoto K, Okamura H, Noda T, Yamauchi T, Itoh H, Ohno S, Motomura H, Ogawa Y, Goto H, Minami T, Yagihara N, Watanabe H, Hasegawa K, Terasawa A, Mikami H, Ogino K, Nakano Y, Imashiro S, Fukushima Y, Tsuzuki Y, Asakura K, Yoshimatsu J, Shiraishi I, Kamakura S, Miyamoto Y, Yasuda S, Akasaka T, Horie M, Shimizu W, Kusano K (2017) Arrhythmia risk and beta-blocker therapy in pregnant women with long QT syndrome. Heart 103(17):1374–1379PubMedCrossRefGoogle Scholar
  40. Isom LL, De Jongh KS, Patton DE, Reber BF, Offord J, Charbonneau H, Walsh K, Goldin AL, Catterall WA (1992) Primary structure and functional expression of the beta1 subunit of the rat brain sodium channel. Science 256:839–842PubMedPubMedCentralCrossRefGoogle Scholar
  41. Isom LL, Ragsdale DS, De Jongh KS, Westenbroek RE, Reber BF, Scheuer T, Catterall WA (1995) Structure and function of the beta2 subunit of brain sodium channels, a transmembrane glycoprotein with a CAM motif. Cell 83:433–442PubMedPubMedCentralCrossRefGoogle Scholar
  42. Kapplinger JD, Giudicessi JR, Ye D, Tester DJ, Callis TE, Valdivia CR, Makielski JC, Wilde AA, Ackerman MJ (2015) Enhanced classification of Brugada syndrome-associated and long-QT syndrome-associated genetic variants in the SCN5A-encoded Na(v)1.5 cardiac sodium channel. Circ Cardiovasc Genet 8:582–595PubMedPubMedCentralCrossRefGoogle Scholar
  43. Khaliulin I, Bond M, James AF, Dyar Z, Amini R, Johnson JL, Suleiman MS (2017) Functional and cardioprotective effects of simultaneous and individual activation of protein kinase A and Epac. Br J Pharmacol 174:438–453PubMedPubMedCentralCrossRefGoogle Scholar
  44. Klaver EC, Versluijs GM, Wilders R (2011) Cardiac ion channel mutations in the sudden infant death syndrome. Int J Cardiol 152:162–170PubMedCrossRefGoogle Scholar
  45. Ko SH, Lenkowski PW, Lee HC, Mounsey JP, Patel MK (2005) Modulation of Na(v)1.5 by beta1- and beta3-subunit co-expression in mammalian cells. Pflugers Arch 449:403–412PubMedPubMedCentralCrossRefGoogle Scholar
  46. Kruger LC, Isom LL (2016) Voltage-gated Na+ channels: not just for conduction. Cold Spring Harb Perspect Biol 8Google Scholar
  47. Kyndt F, Probst V, Potet F, Demolombe S, Chevallier JC, Baro I, Moisan JP, Boisseau P, Schott JJ, Escande D, Le Marec H (2001) Novel SCN5A mutation leading either to isolated cardiac conduction defect or Brugada syndrome in a large French family. Circulation 104:3081–3086PubMedCrossRefGoogle Scholar
  48. Li M, West JW, Numann R, Murphy BJ, Scheuer T, Catterall WA (1993) Convergent regulation of sodium channels by protein kinase C and cAMP-dependent protein kinase. Science 261:1439–1442PubMedPubMedCentralCrossRefGoogle Scholar
  49. Liu M, Sanyal S, Gao G, Gurung IS, Zhu X, Gaconnet G, Kerchner LJ, Shang LL, Huang CL, Grace A, London B, Dudley SC Jr (2009) Cardiac Na+ current regulation by pyridine nucleotides. Circ Res 105:737–745PubMedPubMedCentralCrossRefGoogle Scholar
  50. Liu M, Gu L, Sulkin MS, Liu H, Jeong EM, Greener I, Xie A, Efimov IR, Dudley SC Jr (2013) Mitochondrial dysfunction causing cardiac sodium channel downregulation in cardiomyopathy. J Mol Cell Cardiol 54:25–34PubMedCrossRefGoogle Scholar
  51. Liu M, Shi G, Yang KC, Gu L, Kanthasamy AG, Anantharam V, Dudley SC Jr (2017) Role of protein kinase C in metabolic regulation of the cardiac Na+ channel. Heart Rhythm 14:440–447PubMedCrossRefGoogle Scholar
  52. London B, Michalec M, Mehdi H, Zhu X, Kerchner L, Sanyal S, Viswanathan PC, Pfahnl AE, Shang LL, Madhusudanan M, Baty CJ, Lagana S, Aleong R, Gutmann R, Ackerman MJ, McNamara DM, Weiss R, Dudley SC Jr (2007) Mutation in glycerol-3-phosphate dehydrogenase 1 like gene (GPD1-L) decreases cardiac Na+ current and causes inherited arrhythmias. Circulation 116:2260–2268PubMedPubMedCentralCrossRefGoogle Scholar
  53. Lopez-Santiago LF, Meadows LS, Ernst SJ, Chen C, Malhotra JD, McEwen DP, Speelman A, Noebels JL, Maier SK, Lopatin AN, Isom LL (2007) Sodium channel Scn1b null mice exhibit prolonged QT and RR intervals. J Mol Cell Cardiol 43:636–647PubMedPubMedCentralCrossRefGoogle Scholar
  54. Loussouarn G, Sternberg D, Nicole S, Marionneau C, Le Bouffant F, Toumaniantz G, Barc J, Malak OA, Fressart V, Pereon Y, Baro I, Charpentier F (2015) Physiological and pathophysiological insights of Nav1.4 and Nav1.5 comparison. Front Pharmacol 6:314PubMedGoogle Scholar
  55. Luo L, Ning F, Du Y, Song B, Yang D, Salvage SC, Wang Y, Fraser JA, Zhang S, Ma A, Wang T (2017) Calcium-dependent Nedd4-2 upregulation mediates degradation of the cardiac sodium channel Nav1.5: implications for heart failure. Acta Physiol (Oxf) 221(1):44–58CrossRefGoogle Scholar
  56. Marionneau C, Lichti CF, Lindenbaum P, Charpentier F, Nerbonne JM, Townsend RR, Merot J (2012) Mass spectrometry-based identification of native cardiac Nav1.5 channel alpha subunit phosphorylation sites. J Proteome Res 11:5994–6007PubMedPubMedCentralCrossRefGoogle Scholar
  57. Mathieu S, El Khoury N, Rivard K, Gelinas R, Goyette P, Paradis P, Nemer M, Fiset C (2016) Reduction in Na(+) current by angiotensin II is mediated by PKCalpha in mouse and human-induced pluripotent stem cell-derived cardiomyocytes. Heart Rhythm 13:1346–1354PubMedCrossRefGoogle Scholar
  58. Matsuda JJ, Lee H, Shibata EF (1992) Enhancement of rabbit cardiac sodium channels by beta-adrenergic stimulation. Circ Res 70:199–207PubMedCrossRefGoogle Scholar
  59. Milstein ML, Musa H, Balbuena DP, Anumonwo JM, Auerbach DS, Furspan PB, Hou L, Hu B, Schumacher SM, Vaidyanathan R, Martens JR, Jalife J (2012) Dynamic reciprocity of sodium and potassium channel expression in a macromolecular complex controls cardiac excitability and arrhythmia. Proc Natl Acad Sci U S A 109:E2134–E2143PubMedPubMedCentralCrossRefGoogle Scholar
  60. Moreau A, Keller DI, Huang H, Fressart V, Schmied C, Timour Q, Chahine M (2012) Mexiletine differentially restores the trafficking defects caused by two brugada syndrome mutations. Front Pharmacol 3:62PubMedPubMedCentralCrossRefGoogle Scholar
  61. Moreau A, Boutjdir M, Chahine M (2017) Induced pluripotent stem cell-derived cardiomyocytes: cardiac applications, opportunities and challenges. Can J Physiol Pharmacol 28:1–9Google Scholar
  62. Morgan K, Stevens EB, Shah B, Cox PJ, Dixon AK, Lee K, Pinnock RD, Hughes J, Richardson PJ, Mizuguchi K, Jackson AP (2000) Beta3: an additional auxiliary subunit of the voltage-sensitive sodium channel that modulates channel gating with distinct kinetics. Proc Natl Acad Sci U S A 97:2308–2313PubMedPubMedCentralCrossRefGoogle Scholar
  63. Motoike HK, Liu H, Glaaser IW, Yang AS, Tateyama M, Kass RS (2004) The Na+ channel inactivation gate is a molecular complex: a novel role of the COOH-terminal domain. J Gen Physiol 123:155–165PubMedPubMedCentralCrossRefGoogle Scholar
  64. Murphy BJ, Rogers J, Perdichizzi AP, Colvin AA, Catterall WA (1996) cAMP-dependent phosphorylation of two sites in the alpha subunit of the cardiac sodium channel. J Biol Chem 271:28837–28843PubMedCrossRefGoogle Scholar
  65. Murray KT, Hu NN, Daw JR, Shin HG, Watson MT, Mashburn AB, George AL Jr (1997) Functional effects of protein kinase C activation on the human cardiac Na+ channel. Circ Res 80:370–376PubMedPubMedCentralCrossRefGoogle Scholar
  66. Newton AC, Antal CE, Steinberg SF (2016) Protein kinase C mechanisms that contribute to cardiac remodelling. Clin Sci (Lond) 130:1499–1510CrossRefGoogle Scholar
  67. Nielsen MW, Holst AG, Olesen SP, Olesen MS (2013) The genetic component of Brugada syndrome. Front Physiol 4:179PubMedPubMedCentralCrossRefGoogle Scholar
  68. Numann R, Catterall WA, Scheuer T (1991) Functional modulation of brain sodium channels by protein kinase C phosphorylation. Science 254:115–118PubMedPubMedCentralCrossRefGoogle Scholar
  69. Nuyens D, Stengl M, Dugarmaa S, Rossenbacker T, Compernolle V, Rudy Y, Smits JF, Flameng W, Clancy CE, Moons L, Vos MA, Dewerchin M, Benndorf K, Collen D, Carmeliet E, Carmeliet P (2001) Abrupt rate accelerations or premature beats cause life-threatening arrhythmias in mice with long-QT3 syndrome. Nat Med 7:1021–1027PubMedCrossRefGoogle Scholar
  70. Ono K, Kiyosue T, Arita M (1989) Isoproterenol, DBcAMP, and forskolin inhibit cardiac sodium current. Am J Phys 256:C1131–C1137CrossRefGoogle Scholar
  71. Ono K, Fozzard HA, Hanck DA (1993) Mechanism of cAMP-dependent modulation of cardiac sodium channel current kinetics. Circ Res 72:807–815PubMedCrossRefGoogle Scholar
  72. Peeters U, Scornik F, Riuro H, Perez G, Komurcu-Bayrak E, Van Malderen S, Pappaert G, Tarradas A, Pagans S, Daneels D, Breckpot K, Brugada P, Bonduelle M, Brugada R, Van Dooren S (2015) Contribution of cardiac sodium channel beta-subunit variants to Brugada syndrome. Circ J 79:2118–2129PubMedCrossRefGoogle Scholar
  73. Perrino C, Schroder JN, Lima B, Villamizar N, Nienaber JJ, Milano CA, Naga Prasad SV (2007) Dynamic regulation of phosphoinositide 3-kinase-gamma activity and beta-adrenergic receptor trafficking in end-stage human heart failure. Circulation 116:2571–2579PubMedCrossRefGoogle Scholar
  74. Petitprez S, Zmoos AF, Ogrodnik J, Balse E, Raad N, El-Haou S, Albesa M, Bittihn P, Luther S, Lehnart SE, Hatem SN, Coulombe A, Abriel H (2011) SAP97 and dystrophin macromolecular complexes determine two pools of cardiac sodium channels Nav1.5 in cardiomyocytes. Circ Res 108:294–304PubMedPubMedCentralCrossRefGoogle Scholar
  75. Qu Y, Rogers J, Tanada T, Scheuer T, Catterall WA (1994) Modulation of cardiac Na+ channels expressed in a mammalian cell line and in ventricular myocytes by protein kinase C. Proc Natl Acad Sci U S A 91:3289–3293PubMedPubMedCentralCrossRefGoogle Scholar
  76. Qu Y, Rogers JC, Chen SF, McCormick KA, Scheuer T, Catterall WA (1999) Functional roles of the extracellular segments of the sodium channel alpha subunit in voltage-dependent gating and modulation by beta1 subunits. J Biol Chem 274:32647–32654PubMedPubMedCentralCrossRefGoogle Scholar
  77. Riuro H, Beltran-Alvarez P, Tarradas A, Selga E, Campuzano O, Verges M, Pagans S, Iglesias A, Brugada J, Brugada P, Vazquez FM, Perez GJ, Scornik FS, Brugada R (2013) A missense mutation in the sodium channel beta2 subunit reveals SCN2B as a new candidate gene for Brugada syndrome. Hum Mutat 34:961–966PubMedPubMedCentralCrossRefGoogle Scholar
  78. Ruan Y, Liu N, Bloise R, Napolitano C, Priori SG (2007) Gating properties of SCN5A mutations and the response to mexiletine in long-QT syndrome type 3 patients. Circulation 116:1137–1144PubMedCrossRefGoogle Scholar
  79. Ruan Y, Liu N, Priori SG (2009) Sodium channel mutations and arrhythmias. Nat Rev Cardiol 6:337–348PubMedCrossRefGoogle Scholar
  80. Schreibmayer W (1999) Isoform diversity and modulation of sodium channels by protein kinases. Cell Physiol Biochem 9:187–200PubMedCrossRefGoogle Scholar
  81. Schreibmayer W, Frohnwieser B, Dascal N, Platzer D, Spreitzer B, Zechner R, Kallen RG, Lester HA (1994) Beta-adrenergic modulation of currents produced by rat cardiac Na+ channels expressed in Xenopus laevis oocytes. Receptors Channels 2:339–350PubMedGoogle Scholar
  82. Schubert B, Vandongen AM, Kirsch GE, Brown AM (1990) Inhibition of cardiac Na+ currents by isoproterenol. Am J Phys 258:H977–H982Google Scholar
  83. Schwartz PJ, Stramba-Badiale M, Crotti L, Pedrazzini M, Besana A, Bosi G, Gabbarini F, Goulene K, Insolia R, Mannarino S, Mosca F, Nespoli L, Rimini A, Rosati E, Salice P, Spazzolini C (2009) Prevalence of the congenital long-QT syndrome. Circulation 120(18):1761–1767PubMedPubMedCentralCrossRefGoogle Scholar
  84. Schwartz PJ, Ackerman MJ (2013) The long QT syndrome: a transatlantic clinical approach to diagnosis and therapy. Eur Heart J 34:3109–3116PubMedCrossRefGoogle Scholar
  85. Shi Q, Li M, Mika D, Fu Q, Kim S, Phan J, Shen A, Vandecasteele G, Xiang YK (2017) Heterologous desensitization of cardiac beta-adrenergic signal via hormone-induced betaAR/arrestin/PDE4 complexes. Cardiovasc Res 113:656–670PubMedPubMedCentralCrossRefGoogle Scholar
  86. Shin HG, Murray KT (2001) Conventional protein kinase C isoforms and cross-activation of protein kinase A regulate cardiac Na+ current. FEBS Lett 495:154–158PubMedPubMedCentralCrossRefGoogle Scholar
  87. Shin HG, Barnett JV, Chang P, Reddy S, Drinkwater DC, Pierson RN, Wiley RG, Murray KT (2000) Molecular heterogeneity of protein kinase C expression in human ventricle. Cardiovasc Res 48:285–299PubMedCrossRefGoogle Scholar
  88. Smith FD, Esseltine JL, Nygren PJ, Veesler D, Byrne DP, Vonderach M, Strashnov I, Eyers CE, Eyers PA, Langeberg LK, Scott JD (2017) Local protein kinase A action proceeds through intact holoenzymes. Science 356:1288–1293PubMedPubMedCentralCrossRefGoogle Scholar
  89. Srivastava U, Aromolaran AS, Fabris F, Lazaro D, Kassotis J, Qu Y, Boutjdir M (2016) Novel function of alpha1D L-type calcium channel in the atria. Biochem Biophys Res Commun 482(4):771–776PubMedCrossRefGoogle Scholar
  90. Sunami A, Fan Z, Nakamura F, Naka M, Tanaka T, Sawanobori T, Hiraoka M (1991) The catalytic subunit of cyclic AMP-dependent protein kinase directly inhibits sodium channel activities in guinea-pig ventricular myocytes. Pflugers Arch 419:415–417PubMedCrossRefGoogle Scholar
  91. Tateyama M, Kurokawa J, Terrenoire C, Rivolta I, Kass RS (2003) Stimulation of protein kinase C inhibits bursting in disease-linked mutant human cardiac sodium channels. Circulation 107:3216–3222PubMedCrossRefGoogle Scholar
  92. Triposkiadis F, Karayannis G, Giamouzis G, Skoularigis J, Louridas G, Butler J (2009) The sympathetic nervous system in heart failure physiology, pathophysiology, and clinical implications. J Am Coll Cardiol 54:1747–1762PubMedCrossRefGoogle Scholar
  93. Turnham RE, Scott JD (2016) Protein kinase A catalytic subunit isoform PRKACA; history, function and physiology. Gene 577:101–108PubMedCrossRefGoogle Scholar
  94. Ulbricht W (2005) Sodium channel inactivation: molecular determinants and modulation. Physiol Rev 85:1271–1301PubMedPubMedCentralCrossRefGoogle Scholar
  95. Valdivia CR, Tester DJ, Rok BA, Porter CB, Munger TM, Jahangir A, Makielski JC, Ackerman MJ (2004) A trafficking defective, Brugada syndrome-causing SCN5A mutation rescued by drugs. Cardiovasc Res 62:53–62PubMedPubMedCentralCrossRefGoogle Scholar
  96. Valdivia CR, Ueda K, Ackerman MJ, Makielski JC (2009) GPD1L links redox state to cardiac excitability by PKC-dependent phosphorylation of the sodium channel SCN5A. Am J Physiol Heart Circ Physiol 297:H1446–H1452PubMedPubMedCentralCrossRefGoogle Scholar
  97. Van Norstrand DW, Valdivia CR, Tester DJ, Ueda K, London B, Makielski JC, Ackerman MJ (2007) Molecular and functional characterization of novel glycerol-3-phosphate dehydrogenase 1 like gene (GPD1-L) mutations in sudden infant death syndrome. Circulation 116:2253–2259PubMedPubMedCentralCrossRefGoogle Scholar
  98. Viswanathan PC, Bezzina CR, George AL Jr, Roden DM, Wilde AA, Balser JR (2001) Gating-dependent mechanisms for flecainide action in SCN5A-linked arrhythmia syndromes. Circulation 104:1200–1205PubMedCrossRefGoogle Scholar
  99. Wang DW, Makita N, Kitabatake A, Balser JR, George AL Jr (2000) Enhanced Na(+) channel intermediate inactivation in Brugada syndrome. Circ Res 87:e37–e43PubMedCrossRefGoogle Scholar
  100. Ward CA, Giles WR (1997) Ionic mechanism of the effects of hydrogen peroxide in rat ventricular myocytes. J Physiol 500(3):631–642PubMedPubMedCentralCrossRefGoogle Scholar
  101. Watanabe H, Koopmann TT, Le Scouarnec S, Yang T, Ingram CR, Schott JJ, Demolombe S, Probst V, Anselme F, Escande D, Wiesfeld AC, Pfeufer A, Kaab S, Wichmann HE, Hasdemir C, Aizawa Y, Wilde AA, Roden DM, Bezzina CR (2008) Sodium channel beta1 subunit mutations associated with Brugada syndrome and cardiac conduction disease in humans. J Clin Invest 118:2260–2268PubMedPubMedCentralGoogle Scholar
  102. Watson CL, Gold MR (1997) Modulation of Na+ current inactivation by stimulation of protein kinase C in cardiac cells. Circ Res 81:380–386CrossRefPubMedPubMedCentralGoogle Scholar
  103. Weber S, Meyer-Roxlau S, Wagner M, Dobrev D, El-Armouche A (2015) Counteracting protein kinase activity in the heart: the multiple roles of protein phosphatases. Front Pharmacol 6:270PubMedPubMedCentralCrossRefGoogle Scholar
  104. Wetsel WC, Khan WA, Merchenthaler I, Rivera H, Halpern AE, Phung HM, Negro-Vilar A, Hannun YA (1992) Tissue and cellular distribution of the extended family of protein kinase C isoenzymes. J Cell Biol 117:121–133PubMedCrossRefGoogle Scholar
  105. Wilde AA, Brugada R (2011) Phenotypical manifestations of mutations in the genes encoding subunits of the cardiac sodium channel. Circ Res 108:884–897PubMedPubMedCentralCrossRefGoogle Scholar
  106. Wilde AA, Moss AJ, Kaufman ES, Shimizu W, Peterson DR, Benhorin J, Lopes C, Towbin JA, Spazzolini C, Crotti L, Zareba W, Goldenberg I, Kanters JK, Robinson JL, Qi M, Hofman N, Tester DJ, Bezzina CR, Alders M, Aiba T, Kamakura S, Miyamoto Y, Andrews ML, McNitt S, Polonsky B, Schwartz PJ, Ackerman MJ (2016) Clinical aspects of type 3 long-QT syndrome: an international multicenter study. Circulation 134:872–882PubMedPubMedCentralCrossRefGoogle Scholar
  107. Xiang Y, Kobilka BK (2003) Myocyte adrenoceptor signaling pathways. Science 300:1530–1532PubMedCrossRefGoogle Scholar
  108. Xiao GQ, Qu Y, Sun ZQ, Mochly-Rosen D, Boutjdir M (2001) Evidence for functional role of epsilonPKC isozyme in the regulation of cardiac Na(+) channels. Am J Physiol Cell Physiol 281:C1477–C1486PubMedCrossRefGoogle Scholar
  109. Yu FH, Westenbroek RE, Silos-Santiago I, McCormick KA, Lawson D, Ge P, Ferriera H, Lilly J, DiStefano PS, Catterall WA, Scheuer T, Curtis R (2003) Sodium channel beta4, a new disulfide-linked auxiliary subunit with similarity to beta2. J Neurosci 23:7577–7585PubMedPubMedCentralCrossRefGoogle Scholar
  110. Zhou J, Yi J, Hu N, George AL Jr, Murray KT (2000) Activation of protein kinase A modulates trafficking of the human cardiac sodium channel in Xenopus oocytes. Circ Res 87:33–38PubMedCrossRefGoogle Scholar
  111. Zhou J, Shin HG, Yi J, Shen W, Williams CP, Murray KT (2002) Phosphorylation and putative ER retention signals are required for protein kinase A-mediated potentiation of cardiac sodium current. Circ Res 91(6):540PubMedPubMedCentralCrossRefGoogle Scholar
  112. Zimmer T, Benndorf K (2007) The intracellular domain of the beta2 subunit modulates the gating of cardiac Nav1.5 channels. Biophys J 92:3885–3892PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Ademuyiwa S. Aromolaran
    • 1
    • 2
  • Mohamed Chahine
    • 3
    • 4
  • Mohamed Boutjdir
    • 1
    • 2
    • 5
    Email author
  1. 1.Cardiovascular Research Program, VA New York Harbor Healthcare SystemBrooklynUSA
  2. 2.Departments of Medicine, Cell Biology and PharmacologyState University of New York Downstate Medical CenterBrooklynUSA
  3. 3.CERVO Brain Research CenterInstitut Universitaire en Santé Mentale de QuébecQuebec CityCanada
  4. 4.Department of MedicineUniversité LavalQuebec CityCanada
  5. 5.Department of MedicineNew York University School of MedicineNew YorkUSA

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