Regulation of Calcium Slow Channels in Cardiac Muscle and Vascular Smooth Muscle Cells

  • Nicholas Sperelakis
  • Noritsugu Tohse
  • Yusuke Ohya
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 311)


Considerable attention during the past few years has been given to phosphorylation of ion channels as a means whereby the activity of the ion channels can be regulated. This article will cover the evidence that cyclic nucleotides regulate the Ca2+ influx into the myocardial cells during each cardiac cycle and into vascular smooth muscle (VSM) cells. This regulation is presumable mediated by phosphorylation(s) of the Ca2+ slow channel protein and/or of associated regulatory protein(s). In myocardial cells, such phosphorylation (Fig. 1) presumably (a) increases the number of Ca2+ slow channels available for voltage activation during the action potential (AP); (b) increases the probability of their opening, and (c) increases their mean open time. A greater density of available Ca2+ channels increases Ca2+ influx and inward Ca2+ slow current (Isi) during the AP, and so increases the force of contraction of the heart. In some VSM cells, phosphorylation by cAMP-PK or cGMP-PK inhibits the Ca2+ slow channel activity and thereby produces vasodilation, whereas phosphorylation by PK-C stimulates the Ca2+ slow channel activity and produces vasoconstriction.


Atrial Natriuretic Peptide Phorbol Ester Cyclic Nucleotide Slow Channel Positive Inotropic Agent 
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  1. Aaronson, P.L, Benham, C.D., Bolton, T.B., Hess, P., Lang, R.J., and Tsien, F.W., 1986, Two types of single-channel and whole-cell calcium or barium currents in single smooth muscle cells of rabbit ear artery and the effects of noradrenaline, J. Physiol., 377:36.Google Scholar
  2. Armstrong, D. and Eckert, R., 1987, Voltage-activated calcium channels that must be phosphorylated to respond to membrane depolarization, Proc. Natl. Acad. Sci., USA, 84:2518–2522.PubMedCrossRefGoogle Scholar
  3. Bean, B., 1985, Two kinds of calcium channels in canine atrial cells, Differences in kinetics, selectivity, and pharmacology, J. Gen. Physiol., 86:1–30.PubMedCrossRefGoogle Scholar
  4. Bean, B.P., Nowycky, M.C., and Tsien, R.W., 1984, Beta-adrenergic modulation of calcium channels in frog ventricular heart cells, Nature, 307:371–375.PubMedCrossRefGoogle Scholar
  5. Bean, B.P., Sturek, M., Puga, A., and Hermsmeyer, K., 1986, Calcium channels in muscle cells isolated from rat mesenteric arteries: Modulation by dihydropyridine drugs, Circ. Res., 59:229–235.PubMedCrossRefGoogle Scholar
  6. Berridge, M.J. and Irvine, R.F., 1984, Inositol trisphosphate, a novel second messenger in cellular signal transduction, Nature, 312:315–321.PubMedCrossRefGoogle Scholar
  7. Bkailey, G. and Sperelakis, N., 1984, Injection of protein kinase inhibitor into cultured heart cells blocks calcium slow channels, Am. J. Physiol., 246:H630-H634.Google Scholar
  8. Bkaily, G. and Sperelakis, N., 1985, Injection of cyclic GMP into her cells blocks the slow action potentials, Am. J. Physiol. (Heart Circ. Physiol), 248:H745–H749.Google Scholar
  9. Bkaily, G. and Sperelakis, N., 1986, Calmodulin is required for a full activation of the calcium slow channels in heart cells, J. Cyclic Nucleo. Prot. Phosph. Res., 11:25–34.Google Scholar
  10. Bkaily, G., Peyrow, M., Sculptoreanu, A., Jacques, D., Chahine, M., Regoli, D., and Sperelakis, N., 1988a, Angiotensin II increased Isi and blocks IK in single aortic cell of rabbit, Pflugers Arch., 412:448–450.CrossRefGoogle Scholar
  11. Bkaily, G., Sperelakis, N., and Eldefrawi, M., 1984, Effects of the calmodulin inhibitor, trifluoperazine, on membrane potentials and slow action potentials of cultured heart cells, Europ. J. Pharm., 105:23–31.CrossRefGoogle Scholar
  12. Bkaily, G., Yamamoto, T., Peyrow, M., Sculptoreanu, A., Jacques, D., and Sperelakis, N., 1988b, Macroscopic Ca2+ and K+ currents in single heart and aortic cells, Mol. Cell. Biochem., 80:59–72.PubMedGoogle Scholar
  13. Bolton, T.B., 1979, Mechanisms of action of transmitters and other substances on smooth muscle, Physiol. Rev., 59:606–718.Google Scholar
  14. Brown, A.M. and Birnbaumer, L., 1988, Direct G-protein gating of ion channels, Am. J. Physiol., 254:H401–H410.PubMedGoogle Scholar
  15. Brown, J.H., Buxton, I.L., and Brunton, L.L., 1985, Alpha 1-adrenergic and muscarinic cholinergic stimulation of phosphoinositide hydrolysis in adult rat cardiomyocytes, Circ. Res., 57:532–537.Google Scholar
  16. Bruckner, R. and Scholz, H., 1984, Effects of alpha-adrenoceptor stimulation with phenylephrine in the presence of propranolol on force of contraction, slow inward current and cyclic AMP content in the bovine heart, Br. J. Pharmacol., 82:223–232.PubMedCrossRefGoogle Scholar
  17. Brum, G., Flockerzi, V., Hofmann, F., Osterrieder, W., and Trautwein, W., 1983, Injection of catalytic subunit of cAMP-dependent protein kinase into isolated cardiac myocytes, Pflugers Arch., 398:147–154.PubMedCrossRefGoogle Scholar
  18. Cachelin, A.B., dePeyer, J.E., Kokubun, S., and Reuter, H., 1983, Ca2+ channel modulation by 8-bromo-cyclic AMP in culture heart cells, Nature, 304:462–464.PubMedCrossRefGoogle Scholar
  19. Chad, J.E. and Eckert, R.J., 1986, An ezymatic mechanism for calcium current inactivation in dialysed Helix neurones, J. Physiol., 378:31–51.PubMedGoogle Scholar
  20. Chiu, AT., Bozarth, J.M., Forsyth, M.S., and Timmermans, P.B.M.W.M., 1987, Ca2+ utilization of the constriction of rat aorta to stimulation of protein kinase C by phorbol dibutyrate, J. Pharmacol. Exp. Therap., 242:934.Google Scholar
  21. Cuppoletti, J., Thakkar, J., Sperelakis, N., and Wahler, G., 1988, Cardiac sarcolemmal substrate of the cGMP-dependent protein kinase, Memb. Biochem., 7:135–142.Google Scholar
  22. Danthuluri, N.R. and Deth, R.D., 1986, Acute desensitization to angiotensin II: Evidence for a requirement of agonist-induced diacylglycerol production during tonic contraction of rat aorta, Eur. J. Pharmacol., 125:1103.Google Scholar
  23. Dosemeci, A., Dhalla, R.S., Cohen, N.M., Lederer, W.J., and Rogers, T.B., 1988, Phorbol ester increases calcium current and stimulates the effects of angiotensin II on cultured neonatal rat heart myocytes, Circ. Res., 62:347.PubMedCrossRefGoogle Scholar
  24. Droogmans, G., Declerck, I., and Casteel, R., 1987, Effect of adrenergic agonists on Ca2+ -channel currents in single vascular smooth muscle cells, Pflugers Arch., 409:7–12.PubMedCrossRefGoogle Scholar
  25. Fischmeister, R. and Hartzell, R.C., 1987, J. Physiol., 398:1475–1481.Google Scholar
  26. Fish, R.D., Sperti, G., Colucci, W.S., and Clapham, D.E., 1988, Phorbol ester increases the dihydropyridine-sensitive calcium conductance in a vascular smooth muscle cell line, Circ. Res., 62:1049.PubMedCrossRefGoogle Scholar
  27. Friedman, M.E., Suarez-Kurtz, G., Karzorowski, G.J., Katz, G.M., and Reuben, J.P., 1986, Two calcium currents in a smooth muscle cell line, Am. J. Physiol., 1986:H699–H703.Google Scholar
  28. Gleason, M.M. and Flaim, S.F., 1986, Phorbol ester contracts rabbit thoracic aorta by increasing intracellular calcium and by activating calcium influx, Biochem. Biophysi. Res. Comm., 138:1362.CrossRefGoogle Scholar
  29. Hescheler, J., Mieskes, G., Ruegg, J.C., Takai, A., and Trautwein, W., 1988, Effects of a protein phosphatase inhibitor, okadaic acid, on membrane currents of isolated guinea pig cardiac myocytes, Pflugers Arch., 412:248–252.PubMedCrossRefGoogle Scholar
  30. Hescheler, J., Rosenthal, W., Trautwein, W., and Schultz, G., 1987, The GTP-binding protein, GO, regulates neuronal calcium channels, Nature (London), 325:445–447.CrossRefGoogle Scholar
  31. Irisawa, H. and Kokobun, S., 1983, Modulation by intracellular ATP and cyclic AMP of the slow inward current in isolated single ventricular cells of the guinea pig, J. Physio., 338:321–327.Google Scholar
  32. Itoh, H. and Lederis, K., 1987, Contraction of rat thoracic aorta strips induced by phorbol 12-myristate 13-acetate, Am. J. Physiol., 252:C244.PubMedGoogle Scholar
  33. Johansson, B. and Somlyo, A.P., 1980, Electrophysiology and excitation-contraction coupling, in: Handbook of Physiology, Sect. 2: The Cardiovascular System, Vol. 2, Bethesda, Am. Physiol. Soc., 301–323.Google Scholar
  34. Johns, D.W. and Sperelakis, N., 1990, Angiotensin-II stimulation of Ca2+-dependent action potentials in cultured rat aortic smooth muscle cells, Eur. J. Pharmacol., 187:183–191.PubMedCrossRefGoogle Scholar
  35. Johnson, J.C., Wittenauer, L.A., and Nathan, R.D., 1983, Calmodulin, Ca2+ -antagonists and Ca2+ -transporters in nerve and muscle, J. Neural Trans. Suppl., 18:97–111.Google Scholar
  36. Josephson, I. and Sperelakis, N., 1978, 5′-Guanylimidodiphosphate stimulation of slow Ca2+ current in myocardial cells, J. Mol. Cell. Cardiol., 10:1157–1166.PubMedCrossRefGoogle Scholar
  37. Josephson, I. and Sperelakis, N., 1976, Local anesthetic blockade of Ca2+ -mediated action grafted and organ cultured in vitro, Eur. J. Pharmacol., 40:201–208.PubMedCrossRefGoogle Scholar
  38. Kameyama, M., Hescheler, J., Hofmann, F., and Trautwein, W., 1986, Pflugers Arch., 407:123–128.PubMedCrossRefGoogle Scholar
  39. Kohlhardt, M. and Haap, K., 1978, 8-Bromo-guanosine-3′,5′-monophosphate mimics the effect of acetylcholine on slow response action potential and contractile force in mammalian atrial myocardium, J. Molec. Cell. Cardiol., 10:573–578.CrossRefGoogle Scholar
  40. Kuriyama, H., Ito, Y., Suzuki, H., Kitamura, T., and Itoh, T., 1982, Factors modifying contraction-relaxation cycle in vascular smooth muscle, Am. J. Physiol., 243:H641–H662.PubMedGoogle Scholar
  41. Li, T. and Sperelakis, N., 1983, Stimulation of slow action potentials in guinea pig papillary muscle cells by intracellular injection of cAMP, Gpp(NH)p, and cholera toxin, Circ. Res., 52:111–117.PubMedCrossRefGoogle Scholar
  42. MacLeod, K.M. and Diamond, J., 1986, Effects of the cyclic GMP lowering agent LY83583 on the interaction of carbachol with forskolin in rabbit isolated cardiac preparations, J. Pharmacol. Exp. Therap., 238:313–318.Google Scholar
  43. Mehegan, J.P., Muir, W.W., Unverferth, D.V., Fertel, R.H., and McGuirk, S.M., 1985, Electrophysiological effects of cyclic GMP on canine cardiac Purkinje fibers, J. Cardiovasc. Pharmacol., 7:30–35.PubMedCrossRefGoogle Scholar
  44. Tohse, N. and Sperelakis, N., 1990, Long-lasting openings of single slow (L-type) Ca2+ channels in chick embryonic heart cells, Am. J. Physiol., 259:H639–H642.PubMedGoogle Scholar
  45. Tohse, N. and Sperelakis, N., 1991, Cyclic GMP inhibits the activity of single calcium channels in embryonic chick heart cells, Circ. Res., in press.Google Scholar
  46. Tohse, N. and Sperelakis, N., 1991, Developmental changes in long-opening behaviour of L-type Ca2+ (slow) channels in embryonic chick heart cells, Submitted.Google Scholar
  47. Trautwein, W. and Hoffman, F., 1983, Activation of calcium current by injection of cAMP and catalytic subunit of cAMP-dependent protein kinase, Proc. Internat. Union Physiol. Sci., 15:75–83.Google Scholar
  48. Tsien, R.W., Giles, W., and Greengard, P., 1972, Nature, 240:181–183.Google Scholar
  49. Vogel, S. and Sperelakis, N., 1981, Induction of slow action potentials microiontophoresis of cyclic AMP into heart cells, J. Mol. Cell. Cardiol., 13:51–64.PubMedCrossRefGoogle Scholar
  50. Vogel, S., Sperelakis, N., Josephson, J., and Brooker, G., 1977, Fluoride stimulation of slow Ca2+ current in cardiac muscle, J. Mol. Cell. Cardiol., 9:461–475.PubMedCrossRefGoogle Scholar
  51. Wahler, G.M., Rusch, N.J., and Sperelakis, N., 1990, 8-bromo-cyclic GMP inhibits the calcium channel current in embryonic chick ventricular myocytes, Can. J. Physiol. Pharm., 68:531–534.CrossRefGoogle Scholar
  52. Wahler, G.M. and Sperelakis, N., 1985, Intracellular injection of cyclic GMP depresses cardiac slow action potentials, J. Cyclic Nucleo. Prot. Phos. Res., 10:83–95.Google Scholar
  53. Wahler, G.M. and Sperelakis, N., 1986, Cholinergic attenuation of the electrophysiological effects of forskolin, J. Cyclic Nucleo. Prot. Phosph. Res., 11:1–10.Google Scholar
  54. Werz, M.A. and MacDonald, R.L., 1987, Phorbol esters: Voltage-dependent effects on calcium-dependent action potentials of mouse general and peripheral neurons in cell culture, J. Neurosci., 7:1639–1647.PubMedGoogle Scholar
  55. Yatani, A., Condina, J., Imoto, Y., Reeves, J.P., Birnbaumer, L., and Brown, A.M., 1987, A G-protein directly regulates mammalian cardiac calcium channels, Science, 238:1288–1292.PubMedCrossRefGoogle Scholar
  56. Yatani, A., Seidel, C.L., Allen, J., and Brown, AM., 1987, Whole-cell and single-channel calcium currents of isolated smooth muscle cells from saphenous vein, Circ. Res., 60:523–533.PubMedCrossRefGoogle Scholar
  57. Zelcer, E. and Sperelakis, N., 1981a, Angiotensin induction of active responses in cultured reaggregates of rat aortic smooth muscle cells, Blood Vessels, 18:263–279.Google Scholar

Copyright information

© Springer Science+Business Media New York 1992

Authors and Affiliations

  • Nicholas Sperelakis
    • 1
  • Noritsugu Tohse
    • 1
  • Yusuke Ohya
    • 1
  1. 1.Department of Physiology and BiophysicsUniversity of Cincinnati, College of MedicineUSA

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