The Journal of Physiological Sciences

, Volume 66, Issue 4, pp 327–336 | Cite as

Differences in the control of basal L-type Ca2+ current by the cyclic AMP signaling cascade in frog, rat, and human cardiac myocytes

  • Rimantas Treinys
  • Andrius Bogdelis
  • Lina Rimkutė
  • Jonas Jurevičius
  • Vytenis Arvydas SkeberdisEmail author
Original Paper


β-adrenergic receptors (β-ARs) mediate the positive inotropic effects of catecholamines by cAMP-dependent phosphorylation of the L-type Ca2+ channels (LTCCs), which provide Ca2+ for the initiation and regulation of cell contraction. The overall effect of cAMP-modulating agents on cardiac calcium current (I Ca,L) and contraction depends on the basal activity of LTCCs which, in turn, depends on the basal activities of key enzymes involved in the cAMP signaling cascade. Our current work is a comparative study demonstrating the differences in the basal activities of β-ARs, adenylyl cyclase, phosphodiesterases, phosphatases, and LTCCs in the frog and rat ventricular and human atrial myocytes. The main conclusion is that the basal I Ca,L, and consequently the contractile function of the heart, is secured from unnecessary elevation of its activity and energy consumption at the several “checking-points” of cAMP-dependent signaling cascade and the loading of these “checking-points” may vary in different species and tissues.


Cardiac myocytes L-type Ca2+ channels Adenylyl cyclase Phosphodiesterase Phosphatase Protein kinase A 



We thank Dr. Rodolphe Fischmeister for valuable discussions, Antanas Navalinskas for skillful technical assistance, and Valeryia Mikalayeva for preparation of the cells. This work was supported by an East–West cooperation grant from INSERM, France.

Conflict of interest

The authors declare no competing or financial interests.


  1. 1.
    Bers DM (2002) Cardiac excitation-contraction coupling. Nature 415:198–205CrossRefPubMedGoogle Scholar
  2. 2.
    Bodi I, Mikala G, Koch SE, Akhter SA, Schwartz A (2005) The L-type calcium channel in the heart: the beat goes on. J Clin Invest 115:3306–3317CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Jurevicius J, Fischmeister R (1996) cAMP compartmentation is responsible for a local activation of cardiac Ca2+ channels by beta-adrenergic agonists. Proc Natl Acad Sci USA 93:295–299CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Iancu RV, Ramamurthy G, Warrier S, Nikolaev VO, Lohse MJ et al (2008) Cytoplasmic cAMP concentrations in intact cardiac myocytes. Am J Physiol Cell Physiol 295:C414–C422CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Mika D, Leroy J, Vandecasteele G, Fischmeister R (2012) PDEs create local domains of cAMP signaling. J Mol Cell Cardiol 52:323–329CrossRefPubMedGoogle Scholar
  6. 6.
    Fischmeister R, Hartzell HC (1986) Mechanism of action of acetylcholine on calcium current in single cells from frog ventricle. J Physiol (London) 376:183–202CrossRefGoogle Scholar
  7. 7.
    Verde I, Vandecasteele G, Lezoualc’h F, Fischmeister R (1999) Characterization of the cyclic nucleotide phosphodiesterase subtypes involved in the regulation of the L-type Ca2+ current in rat ventricular myocytes. Br J Pharmacol 127:65–74CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Kirstein M, Rivet-Bastide M, Hatem S, Benardeau A, Mercadier JJ et al (1995) Nitric oxide regulates the calcium current in isolated human atrial myocytes. J Clin Invest 95:794–802CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Fischmeister R, Hartzell HC (1987) Cyclic guanosine 3′,5′-monophosphate regulates the calcium current in single cells from frog ventricle. J Physiol (London) 387:453–472CrossRefGoogle Scholar
  10. 10.
    Skeberdis VA, Jurevicius J, Fischmeister R (1997) Beta-2 adrenergic activation of L-type Ca2+ current in cardiac myocytes. J Pharmacol Exp Ther 283:452–461PubMedGoogle Scholar
  11. 11.
    Skeberdis VA, Jurevicius J, Fischmeister R (1997) Pharmacological characterization of the receptors involved in the beta-adrenoceptor-mediated stimulation of the L-type Ca2+ current in frog ventricular myocytes. Br J Pharmacol 121:1277–1286CrossRefPubMedGoogle Scholar
  12. 12.
    Kuznetsov V, Pak E, Robinson RB, Steinberg SF (1995) Beta 2-adrenergic receptor actions in neonatal and adult rat ventricular myocytes. Circ Res 76:40–52CrossRefPubMedGoogle Scholar
  13. 13.
    Xiao RP, Zhu W, Zheng M, Chakir K, Bond R et al (2004) Subtype-specific beta-adrenoceptor signaling pathways in the heart and their potential clinical implications. Trends Pharmacol Sci 25:358–365CrossRefPubMedGoogle Scholar
  14. 14.
    Abi-Gerges N, Tavernier B, Mebazaa A, Faivre V, Paqueron X et al (1999) Sequential changes in autonomic regulation of cardiac myocytes after in vivo endotoxin injection in rat. Am J Respir Crit Care Med 160:1196–1204CrossRefPubMedGoogle Scholar
  15. 15.
    Hartzell HC, Mery PF, Fischmeister R, Szabo G (1991) Sympathetic regulation of cardiac calcium current is due exclusively to cAMP-dependent phosphorylation. Nature 351:573–576CrossRefPubMedGoogle Scholar
  16. 16.
    Skeberdis VA, Gendviliene V, Zablockaite D, Treinys R, Macianskiene R et al (2008) beta3-adrenergic receptor activation increases human atrial tissue contractility and stimulates the L-type Ca2+ current. J Clin Invest 118:3219–3227PubMedPubMedCentralGoogle Scholar
  17. 17.
    Chidiac P, Hebert TE, Valiquette M, Dennis M, Bouvier M (1994) Inverse agonist activity of beta-adrenergic antagonists. Mol Pharmacol 45:490–499PubMedGoogle Scholar
  18. 18.
    Vandecasteele G, Eschenhagen T, Fischmeister R (1998) Role of the NO-cGMP pathway in the muscarinic regulation of the L-type Ca2+ current in human atrial myocytes. J Physiol (London) 506(Pt 3):653–663CrossRefGoogle Scholar
  19. 19.
    Bett GC, Dai S, Campbell DL (2002) Cholinergic modulation of the basal L-type calcium current in ferret right ventricular myocytes. J Physiol (London) 542:107–117CrossRefGoogle Scholar
  20. 20.
    Tijskens P, Meissner G, Franzini-Armstrong C (2003) Location of ryanodine and dihydropyridine receptors in frog myocardium. Biophys J 84:1079–1092CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Rozec B, Gauthier C (2006) beta3-adrenoceptors in the cardiovascular system: putative roles in human pathologies. Pharmacol Ther 111:652–673CrossRefPubMedGoogle Scholar
  22. 22.
    Seibold A, Williams B, Huang ZF, Friedman J, Moore RH et al (2000) Localization of the sites mediating desensitization of the beta(2)-adrenergic receptor by the GRK pathway. Mol Pharmacol 58:1162–1173PubMedGoogle Scholar
  23. 23.
    Rapacciuolo A, Suvarna S, Barki-Harrington L, Luttrell LM, Cong M et al (2003) Protein kinase A and G protein-coupled receptor kinase phosphorylation mediates beta-1 adrenergic receptor endocytosis through different pathways. J Biol Chem 278:35403–35411CrossRefPubMedGoogle Scholar
  24. 24.
    Patel PA, Tilley DG, Rockman HA (2009) Physiologic and cardiac roles of beta-arrestins. J Mol Cell Cardiol 46:300–308CrossRefPubMedGoogle Scholar
  25. 25.
    Small KM, McGraw DW, Liggett SB (2003) Pharmacology and physiology of human adrenergic receptor polymorphisms. Ann Review Pharmacol Toxicol 43:381–411CrossRefGoogle Scholar
  26. 26.
    Brodde OE (1993) Beta-adrenoceptors in cardiac disease. Pharmacol Ther 60:405–430CrossRefPubMedGoogle Scholar
  27. 27.
    Farrukh HM, White M, Port JD, Handwerger D, Larrabee P et al (1993) Up-regulation of beta 2-adrenergic receptors in previously transplanted, denervated non-failing human hearts. J Am Coll Cardiol 22:1902–1908CrossRefPubMedGoogle Scholar
  28. 28.
    Moniotte S, Kobzik L, Feron O, Trochu JN, Gauthier C et al (2001) Upregulation of beta(3)-adrenoceptors and altered contractile response to inotropic amines in human failing myocardium. Circulation 103:1649–1655CrossRefPubMedGoogle Scholar
  29. 29.
    Wieland T, Herzig S (2006) Specificity and diversity in Gi/o-mediated signaling: how the heart operates the RGS brake pedal. Circ Res 98:585–586CrossRefPubMedGoogle Scholar
  30. 30.
    Pavan B, Biondi C, Dalpiaz A (2009) Adenylyl cyclases as innovative therapeutic goals. Drug Discov Today 14:982–991CrossRefPubMedGoogle Scholar
  31. 31.
    Cooper DM (2003) Regulation and organization of adenylyl cyclases and cAMP. Biochem J 375:517–529CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Pierre S, Eschenhagen T, Geisslinger G, Scholich K (2009) Capturing adenylyl cyclases as potential drug targets. Nat Rev Drug Discov 8:321–335CrossRefPubMedGoogle Scholar
  33. 33.
    Federman AD, Conklin BR, Schrader KA, Reed RR, Bourne HR (1992) Hormonal stimulation of adenylyl cyclase through Gi-protein beta gamma subunits. Nature 356:159–161CrossRefPubMedGoogle Scholar
  34. 34.
    Mery PF, Abi-Gerges N, Vandecasteele G, Jurevicius J, Eschenhagen T et al (1997) Muscarinic regulation of the L-type calcium current in isolated cardiac myocytes. Life Sci 60:1113–1120CrossRefPubMedGoogle Scholar
  35. 35.
    Omori K, Kotera J (2007) Overview of PDEs and their regulation. Circ Res 100:309–327CrossRefPubMedGoogle Scholar
  36. 36.
    Patrucco E, Albergine MS, Santana LF, Beavo JA (2010) Phosphodiesterase 8A (PDE8A) regulates excitation-contraction coupling in ventricular myocytes. J Mol Cell Cardiol 49:330–333CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Rivet-Bastide M, Vandecasteele G, Hatem S, Verde I, Benardeau A et al (1997) cGMP-stimulated cyclic nucleotide phosphodiesterase regulates the basal calcium current in human atrial myocytes. J Clin Invest 99:2710–2718CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Jurevicius J, Skeberdis VA, Fischmeister R (2003) Role of cyclic nucleotide phosphodiesterase isoforms in cAMP compartmentation following beta2-adrenergic stimulation of ICa, L in frog ventricular myocytes. J Physiol (London) 551:239–252CrossRefGoogle Scholar
  39. 39.
    Guellich A, Mehel H, Fischmeister R (2014) Cyclic AMP synthesis and hydrolysis in the normal and failing heart. Pflugers Arch 466:1163–1175CrossRefPubMedGoogle Scholar
  40. 40.
    Perera RK, Sprenger JU, Steinbrecher JH, Hubscher D, Lehnart SE et al (2015) Microdomain switch of cGMP-regulated phosphodiesterases leads to ANP-induced augmentation of beta-adrenoceptor-stimulated contractility in early cardiac hypertrophy. Circ Res 116:1304–1311CrossRefPubMedGoogle Scholar
  41. 41.
    Maltsev VA, Ji GJ, Wobus AM, Fleischmann BK, Hescheler J (1999) Establishment of beta-adrenergic modulation of L-type Ca2+ current in the early stages of cardiomyocyte development. Circ Res 84:136–145CrossRefPubMedGoogle Scholar
  42. 42.
    Yan X, Gao S, Tang M, Xi J, Gao L et al (2011) Adenylyl cyclase/cAMP-PKA-mediated phosphorylation of basal L-type Ca2+ channels in mouse embryonic ventricular myocytes. Cell Calcium 50:433–443CrossRefPubMedGoogle Scholar
  43. 43.
    Shi Y (2009) Serine/threonine phosphatases: mechanism through structure. Cell 139:468–484CrossRefPubMedGoogle Scholar
  44. 44.
    Wittkopper K, Dobrev D, Eschenhagen T, El-Armouche A (2011) Phosphatase-1 inhibitor-1 in physiological and pathological beta-adrenoceptor signalling. Cardiovasc Res 91:392–401CrossRefPubMedGoogle Scholar
  45. 45.
    Zolnierowicz S (2000) Type 2A protein phosphatase, the complex regulator of numerous signaling pathways. Biochem Pharmacol 60:1225–1235CrossRefPubMedGoogle Scholar
  46. 46.
    Fischmeister R, Castro LR, Abi-Gerges A, Rochais F, Jurevicius J et al (2006) Compartmentation of cyclic nucleotide signaling in the heart: the role of cyclic nucleotide phosphodiesterases. Circ Res 99:816–828CrossRefPubMedGoogle Scholar
  47. 47.
    Wong W, Scott JD (2004) AKAP signalling complexes: focal points in space and time. Nature Rev Mol Cell Biol 5:959–970CrossRefGoogle Scholar
  48. 48.
    Kamide T, Okumura S, Ghosh S, Shinoda Y, Mototani Y et al (2015) Oscillation of cAMP and Ca2+ in cardiac myocytes: a systems biology approach. J Physiol Sci 65:195–200CrossRefPubMedGoogle Scholar
  49. 49.
    Haase H (2007) Ahnak, a new player in beta-adrenergic regulation of the cardiac L-type Ca2+ channel. Cardiovasc Res 73:19–25CrossRefPubMedGoogle Scholar
  50. 50.
    Bogdelis A, Treinys R, Stankevicius E, Jurevicius J, Skeberdis VA (2011) Src family protein tyrosine kinases modulate L-type calcium current in human atrial myocytes. Biochem Biophys Res Commun 413:116–121CrossRefPubMedGoogle Scholar
  51. 51.
    Van der Heyden MA, Wijnhoven TJ, Opthof T (2005) Molecular aspects of adrenergic modulation of cardiac L-type Ca2+ channels. Cardiovasc Res 65:28–39CrossRefPubMedGoogle Scholar
  52. 52.
    Greiser M, Halaszovich CR, Frechen D, Boknik P, Ravens U et al (2007) Pharmacological evidence for altered src kinase regulation of ICa, L in patients with chronic atrial fibrillation. Naunyn-Schmiedeberg’s Arch Pharmacol 375:383–392CrossRefGoogle Scholar
  53. 53.
    Frace AM, Hartzell HC (1993) Opposite effects of phosphatase inhibitors on L-type calcium and delayed rectifier currents in frog cardiac myocytes. J Physiol (London) 472:305–326CrossRefGoogle Scholar
  54. 54.
    Hartzell HC, Hirayama Y, Petit-Jacques J (1995) Effects of protein phosphatase and kinase inhibitors on the cardiac L-type Ca2+ current suggest two sites are phosphorylated by protein kinase A and another protein kinase. J Gen Physiol 106:393–414CrossRefPubMedGoogle Scholar

Copyright information

© The Physiological Society of Japan and Springer Japan 2015

Authors and Affiliations

  • Rimantas Treinys
    • 1
  • Andrius Bogdelis
    • 1
  • Lina Rimkutė
    • 1
  • Jonas Jurevičius
    • 1
  • Vytenis Arvydas Skeberdis
    • 1
    Email author
  1. 1.Institute of CardiologyLithuanian University of Health SciencesKaunasLithuania

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