Voltage-Gated Calcium Channels and Their Roles in Cardiac Electrophysiology

  • Jordi Heijman
  • Cristina E. Molina
  • Niels VoigtEmail author
Part of the Cardiac and Vascular Biology book series (Abbreviated title: Card. vasc. biol.)


In cardiomyocytes voltage-gated Ca2+ channels are major players in cardiac cellular electrophysiology and cellular excitation-contraction coupling. Accordingly, Ca2+ channel dysfunction contributes to the development of cardiac arrhythmias and impaired cardiac contractile function. In addition, Ca2+ entry through voltage-gated Ca2+ channels is an important regulator of gene transcription and cardiac cellular metabolism. In order to fulfil these tasks reliably, Ca2+ channels are highly regulated by specific subunit compositions and various signaling pathways. This chapter provides an overview of the role of voltage-gated Ca2+ channels in cardiac cellular electrophysiology and summarizes their molecular composition, biophysical properties, and regulatory mechanisms, with a special focus on L-type Ca2+ channels.


Calcium Ion channels Action potential Excitation contraction coupling Arrhythmias Early afterdepolarizations 


Compliance with Ethical Standards


N.V. is supported by the DZHK, by the German Research Foundation (DFG VO 1568/3-1, IRTG1816 RP12, SFB1002 TPA13) and by the Else-Kröner-Fresenius Stiftung (EKFS 2016_A20). J.H. is supported by the Netherlands Organization for Scientific Research (NWO/ZonMw Veni 91616057).

Conflict of Interest

Jordi Heijman declares that he has no conflict of interest. Cristina E. Molina declares that she has no conflict of interest. Niels Voigt declares that he has no conflict of interest.

Ethical Approval

This article does not contain any studies with human participants or animals performed by any of the authors.


  1. Abi-Gerges N, Fischmeister R, Mery PF. G protein-mediated inhibitory effect of a nitric oxide donor on the L-type Ca2+ current in rat ventricular myocytes. J Physiol. 2001;531(Pt 1):117–30.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Abi-Gerges N, Szabo G, Otero AS, Fischmeister R, Mery PF. NO donors potentiate the beta-adrenergic stimulation of ICa,L and the muscarinic activation of IK,ACh in rat cardiac myocytes. J Physiol. 2002;540(Pt 2):411–24.CrossRefPubMedPubMedCentralGoogle Scholar
  3. Adams PJ, Snutch TP. Calcium channelopathies: voltage-gated calcium channels. Subcell Biochem. 2007;45:215–51.CrossRefPubMedGoogle Scholar
  4. Alden KJ, Goldspink PH, Ruch SW, Buttrick PM, Garcia J. Enhancement of L-type Ca2+ current from neonatal mouse ventricular myocytes by constitutively active PKC-betaII. Am J Physiol Cell Physiol. 2002;282(4):C768–74. Scholar
  5. Ambrosi CM, Yamada KA, Nerbonne JM, Efimov IR. Gender differences in electrophysiological gene expression in failing and non-failing human hearts. PLoS One. 2013;8(1):e54635. Scholar
  6. Arikkath J, Campbell KP. Auxiliary subunits: essential components of the voltage-gated calcium channel complex. Curr Opin Neurobiol. 2003;13(3):298–307.CrossRefPubMedGoogle Scholar
  7. Balijepalli RC, Foell JD, Hall DD, Hell JW, Kamp TJ. Localization of cardiac L-type Ca2+ channels to a caveolar macromolecular signaling complex is required for beta(2)-adrenergic regulation. Proc Natl Acad Sci U S A. 2006;103(19):7500–5. Scholar
  8. Bartos DC, Grandi E, Ripplinger CM. Ion channels in the heart. Compr Physiol. 2015;5(3):1423–64. Scholar
  9. Benitah JP, Alvarez JL, Gomez AM. L-type Ca2+ current in ventricular cardiomyocytes. J Mol Cell Cardiol. 2010;48(1):26–36. Scholar
  10. Bers DM. Excitation-contraction coupling and cardiac contractile force. 2nd ed. Dordrecht: Springer Science+Business Media; 2001. Scholar
  11. Bers DM. Cardiac excitation-contraction coupling. Nature. 2002;415(6868):198–205. Scholar
  12. Bers DM. Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol. 2008;70:23–49. Scholar
  13. Bers DM, Perez-Reyes E. Ca channels in cardiac myocytes: structure and function in Ca influx and intracellular Ca release. Cardiovasc Res. 1999;42(2):339–60.CrossRefPubMedGoogle Scholar
  14. Best JM, Kamp TJ. Different subcellular populations of L-type Ca2+ channels exhibit unique regulation and functional roles in cardiomyocytes. J Mol Cell Cardiol. 2012;52(2):376–87. Scholar
  15. Betzenhauser MJ, Pitt GS, Antzelevitch C. Calcium channel mutations in cardiac arrhythmia syndromes. Curr Mol Pharmacol. 2015;8(2):133–42.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Bootman MD, Smyrnias I, Thul R, Coombes S, Roderick HL. Atrial cardiomyocyte calcium signalling. Biochim Biophys Acta. 2011;1813(5):922–34. Scholar
  17. Brandenburg S, Kohl T, Williams GS, Gusev K, Wagner E, Rog-Zielinska EA, Hebisch E, Dura M, Didie M, Gotthardt M, Nikolaev VO, Hasenfuss G, Kohl P, Ward CW, Lederer WJ, Lehnart SE. Axial tubule junctions control rapid calcium signaling in atria. J Clin Invest. 2016;126(10):3999–4015. Scholar
  18. Brandmayr J, Poomvanicha M, Domes K, Ding J, Blaich A, Wegener JW, Moosmang S, Hofmann F. Deletion of the C-terminal phosphorylation sites in the cardiac beta-subunit does not affect the basic beta-adrenergic response of the heart and the Ca(v)1.2 channel. J Biol Chem. 2012;287(27):22584–92. Scholar
  19. Capel RA, Terrar DA. The importance of Ca2+-dependent mechanisms for the initiation of the heartbeat. Front Physiol. 2015;6:80. Scholar
  20. Carnes CA, Janssen PM, Ruehr ML, Nakayama H, Nakayama T, Haase H, Bauer JA, Chung MK, Fearon IM, Gillinov AM, Hamlin RL, Van Wagoner DR. Atrial glutathione content, calcium current, and contractility. J Biol Chem. 2007;282(38):28063–73. Scholar
  21. Catterall WA. Structure and regulation of voltage-gated Ca2+ channels. Annu Rev Cell Dev Biol. 2000;16:521–55. Scholar
  22. Catterall WA. Voltage-gated calcium channels. Cold Spring Harb Perspect Biol. 2011;3(8):a003947. Scholar
  23. Chen YH, Li MH, Zhang Y, He LL, Yamada Y, Fitzmaurice A, Shen Y, Zhang H, Tong L, Yang J. Structural basis of the alpha1-beta subunit interaction of voltage-gated Ca2+ channels. Nature. 2004;429(6992):675–80. Scholar
  24. Davies A, Hendrich J, Van Minh AT, Wratten J, Douglas L, Dolphin AC. Functional biology of the alpha(2)delta subunits of voltage-gated calcium channels. Trends Pharmacol Sci. 2007;28(5):220–8. Scholar
  25. Du J, Xie J, Zhang Z, Tsujikawa H, Fusco D, Silverman D, Liang B, Yue L. TRPM7-mediated Ca2+ signals confer fibrogenesis in human atrial fibrillation. Circ Res. 2010;106(5):992–1003. Scholar
  26. Dubel SJ, Altier C, Chaumont S, Lory P, Bourinet E, Nargeot J. Plasma membrane expression of T-type calcium channel alpha(1) subunits is modulated by high voltage-activated auxiliary subunits. J Biol Chem. 2004;279(28):29263–9. Scholar
  27. Eden M, Meder B, Volkers M, Poomvanicha M, Domes K, Branchereau M, Marck P, Will R, Bernt A, Rangrez A, Busch M, German Mouse Clinic C, Hrabe de Angelis M, Heymes C, Rottbauer W, Most P, Hofmann F, Frey N. Myoscape controls cardiac calcium cycling and contractility via regulation of L-type calcium channel surface expression. Nat Commun. 2016;7:11317. Scholar
  28. Fearnley CJ, Roderick HL, Bootman MD. Calcium signaling in cardiac myocytes. Cold Spring Harb Perspect Biol. 2011;3(11):a004242. Scholar
  29. Fulop L, Banyasz T, Magyar J, Szentandrassy N, Varro A, Nanasi PP. Reopening of L-type calcium channels in human ventricular myocytes during applied epicardial action potentials. Acta Physiol Scand. 2004;180(1):39–47. Scholar
  30. Grandi E, Pandit SV, Voigt N, Workman AJ, Dobrev D, Jalife J, Bers DM. Human atrial action potential and Ca2+ model: sinus rhythm and chronic atrial fibrillation. Circ Res. 2011;109(9):1055–66. Scholar
  31. Gray PC, Tibbs VC, Catterall WA, Murphy BJ. Identification of a 15-kDa cAMP-dependent protein kinase-anchoring protein associated with skeletal muscle L-type calcium channels. J Biol Chem. 1997;272(10):6297–302.CrossRefPubMedGoogle Scholar
  32. Greiser M, Neuberger HR, Harks E, El-Armouche A, Boknik P, de Haan S, Verheyen F, Verheule S, Schmitz W, Ravens U, Nattel S, Allessie MA, Dobrev D, Schotten U. Distinct contractile and molecular differences between two goat models of atrial dysfunction: AV block-induced atrial dilatation and atrial fibrillation. J Mol Cell Cardiol. 2009;46(3):385–94. Scholar
  33. Hadley RW, Hume JR. An intrinsic potential-dependent inactivation mechanism associated with calcium channels in guinea-pig myocytes. J Physiol. 1987;389:205–22.CrossRefPubMedPubMedCentralGoogle Scholar
  34. Hagiwara S, Ozawa S, Sand O. Voltage clamp analysis of two inward current mechanisms in the egg cell membrane of a starfish. J Gen Physiol. 1975;65(5):617–44.CrossRefPubMedGoogle Scholar
  35. Han X, Shimoni Y, Giles WR. An obligatory role for nitric oxide in autonomic control of mammalian heart rate. J Physiol. 1994;476(2):309–14.CrossRefPubMedPubMedCentralGoogle Scholar
  36. Han X, Kobzik L, Balligand JL, Kelly RA, Smith TW. Nitric oxide synthase (NOS3)-mediated cholinergic modulation of Ca2+ current in adult rabbit atrioventricular nodal cells. Circ Res. 1996;78(6):998–1008.CrossRefPubMedGoogle Scholar
  37. Harada M, Luo X, Qi XY, Tadevosyan A, Maguy A, Ordog B, Ledoux J, Kato T, Naud P, Voigt N, Shi Y, Kamiya K, Murohara T, Kodama I, Tardif JC, Schotten U, Van Wagoner DR, Dobrev D, Nattel S. Transient receptor potential canonical-3 channel-dependent fibroblast regulation in atrial fibrillation. Circulation. 2012a;126(17):2051–64. Scholar
  38. Harada M, Nattel SN, Nattel S. AMP-activated protein kinase: potential role in cardiac electrophysiology and arrhythmias. Circ Arrhythm Electrophysiol. 2012b;5(4):860–7. Scholar
  39. Harada M, Tadevosyan A, Qi X, Xiao J, Liu T, Voigt N, Karck M, Kamler M, Kodama I, Murohara T, Dobrev D, Nattel S. Atrial fibrillation activates AMP-dependent protein kinase and its regulation of cellular calcium handling: potential role in metabolic adaptation and prevention of progression. J Am Coll Cardiol. 2015;66(1):47–58. Scholar
  40. Hare JM. Nitric oxide and excitation-contraction coupling. J Mol Cell Cardiol. 2003;35(7):719–29.CrossRefPubMedGoogle Scholar
  41. Heijman J, Volders PG, Westra RL, Rudy Y. Local control of beta-adrenergic stimulation: effects on ventricular myocyte electrophysiology and Ca2+-transient. J Mol Cell Cardiol. 2011;50(5):863–71. Scholar
  42. Heijman J, Voigt N, Nattel S, Dobrev D. Cellular and molecular electrophysiology of atrial fibrillation initiation, maintenance, and progression. Circ Res. 2014;114(9):1483–99. Scholar
  43. Heijman J, Erfanian Abdoust P, Voigt N, Nattel S, Dobrev D. Computational models of atrial cellular electrophysiology and calcium handling, and their role in atrial fibrillation. J Physiol. 2016;594(3):537–53. Scholar
  44. Heijman J, Ghezelbash S, Wehrens XH, Dobrev D. Serine/threonine phosphatases in atrial fibrillation. J Mol Cell Cardiol. 2017;103:110–20. Scholar
  45. Hofmann F, Flockerzi V, Kahl S, Wegener JW. L-type CaV1.2 calcium channels: from in vitro findings to in vivo function. Physiol Rev. 2014;94(1):303–26. Scholar
  46. Hohendanner F, Ljubojevic S, MacQuaide N, Sacherer M, Sedej S, Biesmans L, Wakula P, Platzer D, Sokolow S, Herchuelz A, Antoons G, Sipido K, Pieske B, Heinzel FR. Intracellular dyssynchrony of diastolic cytosolic [Ca2+] decay in ventricular cardiomyocytes in cardiac remodeling and human heart failure. Circ Res. 2013;113(5):527–38. Scholar
  47. Hulme JT, Ahn M, Hauschka SD, Scheuer T, Catterall WA. A novel leucine zipper targets AKAP15 and cyclic AMP-dependent protein kinase to the C terminus of the skeletal muscle Ca2+ channel and modulates its function. J Biol Chem. 2002;277(6):4079–87. Scholar
  48. Jay SD, Sharp AH, Kahl SD, Vedvick TS, Harpold MM, Campbell KP. Structural characterization of the dihydropyridine-sensitive calcium channel alpha 2-subunit and the associated delta peptides. J Biol Chem. 1991;266(5):3287–93.PubMedGoogle Scholar
  49. Kamp TJ, Hell JW. Regulation of cardiac L-type calcium channels by protein kinase A and protein kinase C. Circ Res. 2000;87(12):1095–102.CrossRefPubMedGoogle Scholar
  50. Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, Castella M, Diener HC, Heidbuchel H, Hendriks J, Hindricks G, Manolis AS, Oldgren J, Popescu BA, Schotten U, Van Putte B, Vardas P, Agewall S, Camm J, Baron Esquivias G, Budts W, Carerj S, Casselman F, Coca A, De Caterina R, Deftereos S, Dobrev D, Ferro JM, Filippatos G, Fitzsimons D, Gorenek B, Guenoun M, Hohnloser SH, Kolh P, Lip GY, Manolis A, McMurray J, Ponikowski P, Rosenhek R, Ruschitzka F, Savelieva I, Sharma S, Suwalski P, Tamargo JL, Taylor CJ, Van Gelder IC, Voors AA, Windecker S, Zamorano JL, Zeppenfeld K. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Europace. 2016;18(11):1609–78. Scholar
  51. Kirstein M, Rivet-Bastide M, Hatem S, Benardeau A, Mercadier JJ, Fischmeister R. Nitric oxide regulates the calcium current in isolated human atrial myocytes. J Clin Invest. 1995;95(2):794–802. Scholar
  52. Kohlhaas M, Nickel AG, Maack C. Mitochondrial energetics and calcium coupling in the heart. J Physiol. 2017.
  53. Kreusser MM, Backs J. Integrated mechanisms of CaMKII-dependent ventricular remodeling. Front Pharmacol. 2014;5:36. Scholar
  54. Lee KS. Potentiation of the calcium-channel currents of internally perfused mammalian heart cells by repetitive depolarization. Proc Natl Acad Sci U S A. 1987;84(11):3941–5.CrossRefPubMedPubMedCentralGoogle Scholar
  55. Lee TS, Karl R, Moosmang S, Lenhardt P, Klugbauer N, Hofmann F, Kleppisch T, Welling A. Calmodulin kinase II is involved in voltage-dependent facilitation of the L-type Cav1.2 calcium channel: identification of the phosphorylation sites. J Biol Chem. 2006;281(35):25560–7. Scholar
  56. Li D, Melnyk P, Feng J, Wang Z, Petrecca K, Shrier A, Nattel S. Effects of experimental heart failure on atrial cellular and ionic electrophysiology. Circulation. 2000;101(22):2631–8.CrossRefPubMedGoogle Scholar
  57. Ling TY, Wang XL, Chai Q, Lu T, Stulak JM, Joyce LD, Daly RC, Greason KL, Wu LQ, Shen WK, Cha YM, Lee HC. Regulation of cardiac CACNB2 by microRNA-499: potential role in atrial fibrillation. BBA Clin. 2017;7:78–84. Scholar
  58. Makary S, Voigt N, Maguy A, Wakili R, Nishida K, Harada M, Dobrev D, Nattel S. Differential protein kinase C isoform regulation and increased constitutive activity of acetylcholine-regulated potassium channels in atrial remodeling. Circ Res. 2011;109(9):1031–43. Scholar
  59. Mangoni ME, Couette B, Marger L, Bourinet E, Striessnig J, Nargeot J. Voltage-dependent calcium channels and cardiac pacemaker activity: from ionic currents to genes. Prog Biophys Mol Biol. 2006;90(1–3):38–63. Scholar
  60. Martynyuk AE, Kane KA, Cobbe SM, Rankin AC. Role of nitric oxide, cyclic GMP and superoxide in inhibition by adenosine of calcium current in rabbit atrioventricular nodal cells. Cardiovasc Res. 1997;34(2):360–7.CrossRefPubMedGoogle Scholar
  61. Mehel H, Emons J, Vettel C, Wittkopper K, Seppelt D, Dewenter M, Lutz S, Sossalla S, Maier LS, Lechene P, Leroy J, Lefebvre F, Varin A, Eschenhagen T, Nattel S, Dobrev D, Zimmermann WH, Nikolaev VO, Vandecasteele G, Fischmeister R, El-Armouche A. Phosphodiesterase-2 is up-regulated in human failing hearts and blunts beta-adrenergic responses in cardiomyocytes. J Am Coll Cardiol. 2013;62(17):1596–606. Scholar
  62. Mika D, Leroy J, Vandecasteele G, Fischmeister R. PDEs create local domains of cAMP signaling. J Mol Cell Cardiol. 2012;52(2):323–9. Scholar
  63. Mitterdorfer J, Froschmayr M, Grabner M, Striessnig J, Glossmann H. Calcium channels: the beta-subunit increases the affinity of dihydropyridine and Ca2+ binding sites of the alpha 1-subunit. FEBS Lett. 1994;352(2):141–5.CrossRefPubMedGoogle Scholar
  64. Molina CE, Leroy J, Richter W, Xie M, Scheitrum C, Lee IO, Maack C, Rucker-Martin C, Donzeau-Gouge P, Verde I, Llach A, Hove-Madsen L, Conti M, Vandecasteele G, Fischmeister R. Cyclic adenosine monophosphate phosphodiesterase type 4 protects against atrial arrhythmias. J Am Coll Cardiol. 2012;59(24):2182–90. Scholar
  65. Napolitano C, Antzelevitch C. Phenotypical manifestations of mutations in the genes encoding subunits of the cardiac voltage-dependent L-type calcium channel. Circ Res. 2011;108(5):607–18. Scholar
  66. Nattel S, Maguy A, Le Bouter S, Yeh YH. Arrhythmogenic ion-channel remodeling in the heart: heart failure, myocardial infarction, and atrial fibrillation. Physiol Rev. 2007;87(2):425–56. Scholar
  67. Nikolaev VO, Moshkov A, Lyon AR, Miragoli M, Novak P, Paur H, Lohse MJ, Korchev YE, Harding SE, Gorelik J. Beta2-adrenergic receptor redistribution in heart failure changes cAMP compartmentation. Science. 2010;327(5973):1653–7. Scholar
  68. Ono K, Iijima T. Cardiac T-type Ca(2+) channels in the heart. J Mol Cell Cardiol. 2010;48(1):65–70. Scholar
  69. Osadchii O, Norton G, Woodiwiss A. Inotropic responses to phosphodiesterase inhibitors in cardiac hypertrophy in rats. Eur J Pharmacol. 2005;514(2–3):201–8. Scholar
  70. Perez-Reyes E. Molecular physiology of low-voltage-activated t-type calcium channels. Physiol Rev. 2003;83(1):117–61. Scholar
  71. Qi XY, Yeh YH, Xiao L, Burstein B, Maguy A, Chartier D, Villeneuve LR, Brundel BJ, Dobrev D, Nattel S. Cellular signaling underlying atrial tachycardia remodeling of L-type calcium current. Circ Res. 2008;103(8):845–54. Scholar
  72. Qian H, Patriarchi T, Price JL, Matt L, Lee B, Nieves-Cintron M, Buonarati OR, Chowdhury D, Nanou E, Nystoriak MA, Catterall WA, Poomvanicha M, Hofmann F, Navedo MF, Hell JW. Phosphorylation of Ser1928 mediates the enhanced activity of the L-type Ca2+ channel Cav1.2 by the beta2-adrenergic receptor in neurons. Sci Signal. 2017;10(463).
  73. Qin N, Olcese R, Bransby M, Lin T, Birnbaumer L. Ca2+-induced inhibition of the cardiac Ca2+ channel depends on calmodulin. Proc Natl Acad Sci U S A. 1999;96(5):2435–8.CrossRefPubMedPubMedCentralGoogle Scholar
  74. Reuter H. The dependence of slow inward current in Purkinje fibres on the extracellular calcium-concentration. J Physiol. 1967;192(2):479–92.CrossRefPubMedPubMedCentralGoogle Scholar
  75. Reuter H. Localization of beta adrenergic receptors, and effects of noradrenaline and cyclic nucleotides on action potentials, ionic currents and tension in mammalian cardiac muscle. J Physiol. 1974;242(2):429–51.CrossRefPubMedPubMedCentralGoogle Scholar
  76. Reuter H. Properties of two inward membrane currents in the heart. Annu Rev Physiol. 1979;41:413–24. Scholar
  77. Richard S, Leclercq F, Lemaire S, Piot C, Nargeot J. Ca2+ currents in compensated hypertrophy and heart failure. Cardiovasc Res. 1998;37(2):300–11.CrossRefPubMedGoogle Scholar
  78. Richard S, Perrier E, Fauconnier J, Perrier R, Pereira L, Gomez AM, Benitah JP. ‘Ca2+-induced Ca2+ entry’ or how the L-type Ca2+ channel remodels its own signalling pathway in cardiac cells. Prog Biophys Mol Biol. 2006;90(1-3):118–35. Scholar
  79. Richards MA, Clarke JD, Saravanan P, Voigt N, Dobrev D, Eisner DA, Trafford AW, Dibb KM. Transverse tubules are a common feature in large mammalian atrial myocytes including human. Am J Physiol Heart Circ Physiol. 2011;301(5):H1996–2005. Scholar
  80. Ripplinger CM, Noujaim SF, Linz D. The nervous heart. Prog Biophys Mol Biol. 2016;120(1-3):199–209. Scholar
  81. Rivet-Bastide M, Vandecasteele G, Hatem S, Verde I, Benardeau A, Mercadier JJ, Fischmeister R. cGMP-stimulated cyclic nucleotide phosphodiesterase regulates the basal calcium current in human atrial myocytes. J Clin Invest. 1997;99(11):2710–8. Scholar
  82. Rose RA, Backx PH. Calcium channels in the heart. In: Zipes DP, Jalife J, editors. Cardiac electrophysiology – from cell to bedside, vol. 6. New York: Elsevier; 2014. p. 13–22.CrossRefGoogle Scholar
  83. Rose RA, Belke DD, Maleckar MM, Giles WR. Ca2+ entry through TRP-C channels regulates fibroblast biology in chronic atrial fibrillation. Circulation. 2012;126(17):2039–41. Scholar
  84. Rozmaritsa N, Christ T, Van Wagoner DR, Haase H, Stasch JP, Matschke K, Ravens U. Attenuated response of L-type calcium current to nitric oxide in atrial fibrillation. Cardiovasc Res. 2014;101(3):533–42. Scholar
  85. Rusconi F, Ceriotti P, Miragoli M, Carullo P, Salvarani N, Rocchetti M, Di Pasquale E, Rossi S, Tessari M, Caprari S, Cazade M, Kunderfranco P, Chemin J, Bang ML, Polticelli F, Zaza A, Faggian G, Condorelli G, Catalucci D. Peptidomimetic targeting of Cavbeta2 overcomes dysregulation of the L-type calcium channel density and recovers cardiac function. Circulation. 2016;134(7):534–46. Scholar
  86. Sanchez-Alonso JL, Bhargava A, O’Hara T, Glukhov AV, Schobesberger S, Bhogal N, Sikkel MB, Mansfield C, Korchev YE, Lyon AR, Punjabi PP, Nikolaev VO, Trayanova NA, Gorelik J. Microdomain-specific modulation of L-type calcium channels leads to triggered ventricular arrhythmia in heart failure. Circ Res. 2016;119(8):944–55. Scholar
  87. Schram G, Pourrier M, Melnyk P, Nattel S. Differential distribution of cardiac ion channel expression as a basis for regional specialization in electrical function. Circ Res. 2002;90(9):939–50.CrossRefPubMedGoogle Scholar
  88. Shistik E, Ivanina T, Blumenstein Y, Dascal N. Crucial role of N terminus in function of cardiac L-type Ca2+ channel and its modulation by protein kinase C. J Biol Chem. 1998;273(28):17901–9.CrossRefPubMedGoogle Scholar
  89. Soltysinska E, Olesen SP, Christ T, Wettwer E, Varro A, Grunnet M, Jespersen T. Transmural expression of ion channels and transporters in human nondiseased and end-stage failing hearts. Pflugers Arch. 2009;459(1):11–23. Scholar
  90. Song LS, Guatimosim S, Gomez-Viquez L, Sobie EA, Ziman A, Hartmann H, Lederer WJ. Calcium biology of the transverse tubules in heart. Ann N Y Acad Sci. 2005;1047:99–111. Scholar
  91. Sun J, Picht E, Ginsburg KS, Bers DM, Steenbergen C, Murphy E. Hypercontractile female hearts exhibit increased S-nitrosylation of the L-type Ca2+ channel alpha1 subunit and reduced ischemia/reperfusion injury. Circ Res. 2006;98(3):403–11. Scholar
  92. Tamargo J, Caballero R, Gomez R, Delpon E. Cardiac electrophysiological effects of nitric oxide. Cardiovasc Res. 2010;87(4):593–600. Scholar
  93. Tang L, Gamal El-Din TM, Swanson TM, Pryde DC, Scheuer T, Zheng N, Catterall WA. Structural basis for inhibition of a voltage-gated Ca2+ channel by Ca2+ antagonist drugs. Nature. 2016;537(7618):117–21. Scholar
  94. Treinys R, Jurevicius J. L-type Ca2+ channels in the heart: structure and regulation. Medicina (Kaunas). 2008;44(7):491–9.CrossRefGoogle Scholar
  95. Vandecasteele G, Verde I, Rucker-Martin C, Donzeau-Gouge P, Fischmeister R. Cyclic GMP regulation of the L-type Ca2+ channel current in human atrial myocytes. J Physiol. 2001;533(Pt 2):329–40.CrossRefPubMedPubMedCentralGoogle Scholar
  96. Vassort G, Talavera K, Alvarez JL. Role of T-type Ca2+ channels in the heart. Cell Calcium. 2006;40(2):205–20. Scholar
  97. Venetucci L, Denegri M, Napolitano C, Priori SG. Inherited calcium channelopathies in the pathophysiology of arrhythmias. Nat Rev Cardiol. 2012;9(10):561–75. Scholar
  98. Voigt N, Nattel S, Dobrev D. Proarrhythmic atrial calcium cycling in the diseased heart. Adv Exp Med Biol. 2012a;740:1175–91. Scholar
  99. Voigt N, Li N, Wang Q, Wang W, Trafford AW, Abu-Taha I, Sun Q, Wieland T, Ravens U, Nattel S, Wehrens XH, Dobrev D. Enhanced sarcoplasmic reticulum Ca2+ leak and increased Na+-Ca2+ exchanger function underlie delayed after depolarizations in patients with chronic atrial fibrillation. Circulation. 2012b;125(17):2059–70. Scholar
  100. Voigt N, Heijman J, Wang Q, Chiang DY, Li N, Karck M, Wehrens XH, Nattel S, Dobrev D. Cellular and molecular mechanisms of atrial arrhythmogenesis in patients with paroxysmal atrial fibrillation. Circulation. 2014;129(2):145–56. Scholar
  101. Wakili R, Yeh YH, Yan Qi X, Greiser M, Chartier D, Nishida K, Maguy A, Villeneuve LR, Boknik P, Voigt N, Krysiak J, Kaab S, Ravens U, Linke WA, Stienen GJ, Shi Y, Tardif JC, Schotten U, Dobrev D, Nattel S. Multiple potential molecular contributors to atrial hypocontractility caused by atrial tachycardia remodeling in dogs. Circ Arrhythm Electrophysiol. 2010;3(5):530–41. Scholar
  102. Wakili R, Voigt N, Kaab S, Dobrev D, Nattel S. Recent advances in the molecular pathophysiology of atrial fibrillation. J Clin Invest. 2011;121(8):2955–68. Scholar
  103. Wang Y, Wagner MB, Joyner RW, Kumar R. cGMP-dependent protein kinase mediates stimulation of L-type calcium current by cGMP in rabbit atrial cells. Cardiovasc Res. 2000;48(2):310–22.CrossRefPubMedGoogle Scholar
  104. Weiss S, Doan T, Bernstein KE, Dascal N. Modulation of cardiac Ca2+ channel by Gq-activating neurotransmitters reconstituted in Xenopus oocytes. J Biol Chem. 2004;279(13):12503–10. Scholar
  105. Weiss JN, Garfinkel A, Karagueuzian HS, Chen PS, Qu Z. Early afterdepolarizations and cardiac arrhythmias. Heart Rhythm. 2010;7(12):1891–9. Scholar
  106. Wong W, Scott JD. AKAP signalling complexes: focal points in space and time. Nat Rev Mol Cell Biol. 2004;5(12):959–70. Scholar
  107. Yang L, Katchman A, Morrow JP, Doshi D, Marx SO. Cardiac L-type calcium channel (Cav1.2) associates with gamma subunits. FASEB J. 2011;25(3):928–36. Scholar
  108. Yuan WL, Ginsburg KS, Bers DM. Comparison of sarcolemmal calcium channel current in rabbit and rat ventricular myocytes. J Physiol London. 1996;493(3):733–46.CrossRefPubMedGoogle Scholar
  109. Yue Y, Qu Y, Boutjdir M. Beta- and alpha-adrenergic cross-signaling for L-type Ca2+ current is impaired in transgenic mice with constitutive activation of epsilon PKC. Biochem Biophys Res Commun. 2004;314(3):749–54.CrossRefPubMedGoogle Scholar
  110. Yue L, Xie J, Nattel S. Molecular determinants of cardiac fibroblast electrical function and therapeutic implications for atrial fibrillation. Cardiovasc Res. 2011;89(4):744–53. Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Jordi Heijman
    • 1
  • Cristina E. Molina
    • 2
    • 3
  • Niels Voigt
    • 2
    • 3
    Email author
  1. 1.Department of CardiologyCARIM School for Cardiovascular Diseases, Maastricht UniversityMaastrichtThe Netherlands
  2. 2.Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Georg-August University GöttingenGöttingenGermany
  3. 3.DZHK (German Center for Cardiovascular Research)partner site Göttingen, GöttingenGermany

Personalised recommendations