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. 1985 Jul;364:395–411. doi: 10.1113/jphysiol.1985.sp015752

Inactivation of calcium channels in mammalian heart cells: joint dependence on membrane potential and intracellular calcium.

K S Lee, E Marban, R W Tsien
PMCID: PMC1192977  PMID: 2411919

Abstract

Ca channel currents were recorded in Cs-loaded calf cardiac Purkinje fibres and Cs-dialysed myocytes from guinea-pig ventricle to evaluate the dependence of Ca channel inactivation on membrane depolarization and intracellular free Ca concentration ([Ca]i). The decay of Ca channel current during a maintained depolarization was slowed when external Ca was replaced by Sr or Ba. The decay reflected a genuine inactivation of Ca channel conductance, as assessed by the decreased amplitude of inward tail currents following progressively longer depolarizing pulses in ventricular cells. Increasing depolarization slowed inward current inactivation in the presence of extracellular Ca concentration ([Ca]o), but speeded inactivation in the presence of extracellular Ba concentration ([Ba]o), suggesting the participation of fundamentally different mechanisms. Ca channel currents were recorded in Ca-free external solutions to study 'voltage-dependent inactivation'. Inactivation of outward Ca channel current due to Cs efflux was seen with external Ba or in the absence of any permeant divalent cation. With Ca as the charge carrier, increasing [Ca]o speeded the rate of inactivation as expected for [Ca]i-dependent inactivation. The relationship between inactivation and the intracellular Ca transient was assessed by double-pulse experiments. Conditioning pulses that produced maximal inward Ca current and contractile tension left behind more inactivation than either stronger or weaker depolarizations. The agreement between maximal inward current and maximal inactivation remained close when their voltage dependence was shifted along the voltage axis by elevation of [Ca]o. We conclude that inactivation of cardiac Ca channels is both [Ca]i dependent and voltage dependent. The [Ca]i-dependent process may serve as a negative feed-back mechanism for regulating Ca entry into heart cells; the voltage-dependent mechanism may prevent a secondary rise in Ca channel current when intracellular Ca falls during maintained depolarization of cardiac cells.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ahmed Z., Connor J. A. Measurement of calcium influx under voltage clamp in molluscan neurones using the metallochromic dye arsenazo III. J Physiol. 1979 Jan;286:61–82. doi: 10.1113/jphysiol.1979.sp012607. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Aronson R. S. Characteristics of action potentials of hypertrophied myocardium from rats with renal hypertension. Circ Res. 1980 Sep;47(3):443–454. doi: 10.1161/01.res.47.3.443. [DOI] [PubMed] [Google Scholar]
  3. Ashcroft F. M., Stanfield P. R. Calcium inactivation in skeletal muscle fibres of the stick insect, Carausius morosus. J Physiol. 1982 Sep;330:349–372. doi: 10.1113/jphysiol.1982.sp014345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bean B. P., Nowycky M. C., Tsien R. W. Beta-adrenergic modulation of calcium channels in frog ventricular heart cells. 1984 Jan 26-Feb 1Nature. 307(5949):371–375. doi: 10.1038/307371a0. [DOI] [PubMed] [Google Scholar]
  5. Bogdanov K. Y., Zakharov S. I., Rosenshtraukh L. V. Inhibition of the slow response action potential during the aftercontraction in mammalian heart muscle. J Mol Cell Cardiol. 1981 Jul;13(7):655–665. doi: 10.1016/0022-2828(81)90273-x. [DOI] [PubMed] [Google Scholar]
  6. Brown A. M., Morimoto K., Tsuda Y., wilson D. L. Calcium current-dependent and voltage-dependent inactivation of calcium channels in Helix aspersa. J Physiol. 1981 Nov;320:193–218. doi: 10.1113/jphysiol.1981.sp013944. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cachelin A. B., de Peyer J. E., Kokubun S., Reuter H. Ca2+ channel modulation by 8-bromocyclic AMP in cultured heart cells. Nature. 1983 Aug 4;304(5925):462–464. doi: 10.1038/304462a0. [DOI] [PubMed] [Google Scholar]
  8. Cahalan M. D., Hall J. Alamethicin channels incorporated into frog node of ranvier: calcium-induced inactivation and membrane surface charges. J Gen Physiol. 1982 Mar;79(3):411–436. doi: 10.1085/jgp.79.3.411. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cavalié A., Ochi R., Pelzer D., Trautwein W. Elementary currents through Ca2+ channels in guinea pig myocytes. Pflugers Arch. 1983 Sep;398(4):284–297. doi: 10.1007/BF00657238. [DOI] [PubMed] [Google Scholar]
  10. Chandler W. K., Meves H. Evidence for two types of sodium conductance in axons perfused with sodium fluoride solution. J Physiol. 1970 Dec;211(3):653–678. doi: 10.1113/jphysiol.1970.sp009298. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Eckert R., Chad J. E. Inactivation of Ca channels. Prog Biophys Mol Biol. 1984;44(3):215–267. doi: 10.1016/0079-6107(84)90009-9. [DOI] [PubMed] [Google Scholar]
  12. Eckert R., Tillotson D. L., Brehm P. Calcium-mediated control of Ca and K currents. Fed Proc. 1981 Jun;40(8):2226–2232. [PubMed] [Google Scholar]
  13. Fox A. P. Voltage-dependent inactivation of a calcium channel. Proc Natl Acad Sci U S A. 1981 Feb;78(2):953–956. doi: 10.1073/pnas.78.2.953. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Fukushima Y., Hagiwara S. Currents carried by monovalent cations through calcium channels in mouse neoplastic B lymphocytes. J Physiol. 1985 Jan;358:255–284. doi: 10.1113/jphysiol.1985.sp015550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gibbons W. R., Fozzard H. A. Relationships between voltage and tension in sheep cardiac Purkinje fibers. J Gen Physiol. 1975 Mar;65(3):345–365. doi: 10.1085/jgp.65.3.345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. HODGKIN A. L., HUXLEY A. F. A quantitative description of membrane current and its application to conduction and excitation in nerve. J Physiol. 1952 Aug;117(4):500–544. doi: 10.1113/jphysiol.1952.sp004764. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hagiwara S., Byerly L. Calcium channel. Annu Rev Neurosci. 1981;4:69–125. doi: 10.1146/annurev.ne.04.030181.000441. [DOI] [PubMed] [Google Scholar]
  18. Hess P., Tsien R. W. Mechanism of ion permeation through calcium channels. 1984 May 31-Jun 6Nature. 309(5967):453–456. doi: 10.1038/309453a0. [DOI] [PubMed] [Google Scholar]
  19. Isenberg G., Belardinelli L. Ionic basis for the antagonism between adenosine and isoproterenol on isolated mammalian ventricular myocytes. Circ Res. 1984 Sep;55(3):309–325. doi: 10.1161/01.res.55.3.309. [DOI] [PubMed] [Google Scholar]
  20. Josephson I. R., Sanchez-Chapula J., Brown A. M. A comparison of calcium currents in rat and guinea pig single ventricular cells. Circ Res. 1984 Feb;54(2):144–156. doi: 10.1161/01.res.54.2.144. [DOI] [PubMed] [Google Scholar]
  21. Kass R. S., Sanguinetti M. C. Inactivation of calcium channel current in the calf cardiac Purkinje fiber. Evidence for voltage- and calcium-mediated mechanisms. J Gen Physiol. 1984 Nov;84(5):705–726. doi: 10.1085/jgp.84.5.705. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kohlhardt M., Herdey A., Kübler M. Interchangeability of Ca ions and Sr ions as charge carriers of the slow inward current in mammalian myocardial fibres. Pflugers Arch. 1973 Nov 26;344(2):149–158. doi: 10.1007/BF00586548. [DOI] [PubMed] [Google Scholar]
  23. Kurachi Y. The effects of intracellular protons on the electrical activity of single ventricular cells. Pflugers Arch. 1982 Sep;394(3):264–270. doi: 10.1007/BF00589102. [DOI] [PubMed] [Google Scholar]
  24. Lee K. S., Tsien R. W. High selectivity of calcium channels in single dialysed heart cells of the guinea-pig. J Physiol. 1984 Sep;354:253–272. doi: 10.1113/jphysiol.1984.sp015374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Lee K. S., Tsien R. W. Mechanism of calcium channel blockade by verapamil, D600, diltiazem and nitrendipine in single dialysed heart cells. Nature. 1983 Apr 28;302(5911):790–794. doi: 10.1038/302790a0. [DOI] [PubMed] [Google Scholar]
  26. Lee K. S., Tsien R. W. Reversal of current through calcium channels in dialysed single heart cells. Nature. 1982 Jun 10;297(5866):498–501. doi: 10.1038/297498a0. [DOI] [PubMed] [Google Scholar]
  27. Linden J., Brooker G. Properties of cardiac contractions in zero sodium solutions: intracellular free calcium controls slow channel conductance. J Mol Cell Cardiol. 1980 May;12(5):457–478. doi: 10.1016/0022-2828(80)90003-6. [DOI] [PubMed] [Google Scholar]
  28. Lux H. D., Brown A. M. Single channel studies on inactivation of calcium currents. Science. 1984 Jul 27;225(4660):432–434. doi: 10.1126/science.6330896. [DOI] [PubMed] [Google Scholar]
  29. Marban E., Tsien R. W. Effects of nystatin-mediated intracellular ion substitution on membrane currents in calf purkinje fibres. J Physiol. 1982 Aug;329:569–587. doi: 10.1113/jphysiol.1982.sp014320. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Marban E., Tsien R. W. Enhancement of calcium current during digitalis inotropy in mammalian heart: positive feed-back regulation by intracellular calcium? J Physiol. 1982 Aug;329:589–614. doi: 10.1113/jphysiol.1982.sp014321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Mentrard D., Vassort G., Fischmeister R. Calcium-mediated inactivation of the calcium conductance in cesium-loaded frog heart cells. J Gen Physiol. 1984 Jan;83(1):105–131. doi: 10.1085/jgp.83.1.105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Mitchell M. R., Powell T., Terrar D. A., Twist V. W. Characteristics of the second inward current in cells isolated from rat ventricular muscle. Proc R Soc Lond B Biol Sci. 1983 Oct 22;219(1217):447–469. doi: 10.1098/rspb.1983.0084. [DOI] [PubMed] [Google Scholar]
  33. Mitchell M. R., Powell T., Terrar D. A., Twist V. W. Ryanodine prolongs Ca-currents while suppressing contraction in rat ventricular muscle cells. Br J Pharmacol. 1984 Jan;81(1):13–15. doi: 10.1111/j.1476-5381.1984.tb10735.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Plant T. D., Standen N. B., Ward T. A. The effects of injection of calcium ions and calcium chelators on calcium channel inactivation in Helix neurones. J Physiol. 1983 Jan;334:189–212. doi: 10.1113/jphysiol.1983.sp014489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Reuter H., Stevens C. F., Tsien R. W., Yellen G. Properties of single calcium channels in cardiac cell culture. Nature. 1982 Jun 10;297(5866):501–504. doi: 10.1038/297501a0. [DOI] [PubMed] [Google Scholar]
  36. Trautwein W., McDonald T. F. Membrane conductance measurements in cat ventricular muscle. J Mol Cell Cardiol. 1978 Apr;10(4):387–394. doi: 10.1016/0022-2828(78)90385-1. [DOI] [PubMed] [Google Scholar]
  37. Tsien R. W. Calcium channels in excitable cell membranes. Annu Rev Physiol. 1983;45:341–358. doi: 10.1146/annurev.ph.45.030183.002013. [DOI] [PubMed] [Google Scholar]
  38. Weingart R., Kass R. S., Tsien R. W. Is digitalis inotropy associated with enhanced slow inward calcium current? Nature. 1978 Jun 1;273(5661):389–392. doi: 10.1038/273389a0. [DOI] [PubMed] [Google Scholar]
  39. Wier W. G., Isenberg G. Intracellular [Ca2+] transients in voltage clamped cardiac Purkinje fibers. Pflugers Arch. 1982 Jan;392(3):284–290. doi: 10.1007/BF00584312. [DOI] [PubMed] [Google Scholar]

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