Molecular and Cellular Biochemistry

, Volume 253, Issue 1–2, pp 3–13 | Cite as

Regulation of L-type Ca2+ channels in the heart: Overview of recent advances

  • Kaoru Yamaoka
  • Masaki Kameyama


Regulation of L-type Ca2+ channels is complex, because many factors, such as phosphorylation, divalent cations, and proteins, specified or unspecified, have been shown to affect the channel activities. An additional complication is that these factors interact with one another to achieve final outcomes. Recent molecular technologies have helped to shed light on the mechanisms governing the activity of L-type Ca2+ channels. In this review article, three major topics concerning regulation of L-type Ca2+ channels in the heart are discussed, i.e. c-AMP dependent channel phosphorylation, role of magnesium (Mg2+), and the phenomenon of channel run-down.

L-type Ca2+ channel magnesium run-down phosphorylation 


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  1. 1.
    Fabiato A: Calcium-induced release of calcium from the cardiac sarcoplasmic reticulum. Am J Physiol 245: C1-C14, 1983Google Scholar
  2. 2.
    Tsien RW: Adrenaline-like effects of intracellular iontophoresis of cyclic AMP in cardiac Purkinje fibres. Nature New Biol 245: 120-122, 1973Google Scholar
  3. 3.
    Reuter H: Strom-Spannungsbeziehungen von Purkinje-Fasern bei verschiedenen extracellularen Calcium-Konzentrationen und unter Adrenalineinwirkung. [Current-tension relations of Purkinje fibers in different extracellular concentrations of calcium and under the influence of adrenaline. Pflügers Arch Gesamte Physiol Menschen Tiere 287: 357-367, 1966Google Scholar
  4. 4.
    Reuter H: Uber die Wirkung von Adrenalin auf den cellularen Ca-Umsatz des Meerschweinchenvorhofs. [On the effect of adrenaline on the cellular Ca-metabolism in the guinea pig atrium]. Naunyn Schmicdebergs Arch Exp Pathol Pharmakol 251: 401-412, 1965Google Scholar
  5. 5.
    Trautwein W, Hescheler J: Regulation of cardiac L-type calcium current by phosphorylation and G proteins. Annu Rev Physiol 52: 257-274, 1990Google Scholar
  6. 6.
    Yue DT, Herzig S, Marban E: β-adrenergic stimulation of calcium channels occurs by potentiation of high-activity gating modes. Proc Natl Acad Sci USA 87: 753-757, 1990Google Scholar
  7. 7.
    Sculptorcanu A, Rotman E, Takahashi M, Scheuer T, Catterall WA: Voltage-dependent potentiation of the activity of cardiac L-type calcium channel α1 subunits due to phosphorylation by cAMP-dependent protein kinase. Proc Natl Acad Sci USA 90: 10135-10139, 1993Google Scholar
  8. 8.
    Charnet P, Lory P, Bourinet E, Collin T, Nargeot J: cAMP-dependent phosphorylation of the cardiac L-type Ca channel: A missing link? Biochimie 77: 957-962, 1995Google Scholar
  9. 9.
    Gao T, Yatani A, Dell' Acqua ML, Sako H, Green SA, Dascal N, Scott JD, Hosey MM: cAMP-dependent regulation of cardiac L-type Ca2+ channels requires membrane targeting of PKA and phosphorylation of channel subunits. Neuron 19: 185-196, 1997Google Scholar
  10. 10.
    Kameyama A, Shearman MS, Sekiguchi K, Kameyama M: Cyclic AMP-dependent protein kinase but not protein kinase C regulates the cardiac Ca2+ channel through phosphorylation of its α1 subunit. J Biochem (Tokyo) 120: 170-176, 1996Google Scholar
  11. 11.
    Ochi R: Single-channel mechanism of β-adrenergic enhancement of cardiac L-type calcium current. Jpn J Physiol 43: 571-584, 1993Google Scholar
  12. 12.
    Yamaoka K, Seyama I: Phosphorylation modulates L-type Ca channels in frog ventricular myocytes by changes in sensitivity to Mg2+ block. Pflügers Arch 435: 329-337, 1998Google Scholar
  13. 13.
    Bunemann M, Gerhardstein BL, Gao T, Hosey MM: Functional regulation of L-type calcium channels via protein kinase A-mediated phosphorylation of the β2 subunit. J Biol Chem 274: 33851-33854, 1999Google Scholar
  14. 14.
    Mikala G, Klöckner U, Varadi M, Eisfeld J, Schwartz A, Varadi G: cAMP-dependent phosphorylation sites and macroscopic activity of recombinant cardiac L-type calcium channels. Mol Cell Biochem 185: 95-109, 1998Google Scholar
  15. 15.
    Yatani A, Brown AM: Rapid β-adrenergic modulation of cardiac calcium channel currents by a fast G protein pathway. Science 245: 71-74, 1989Google Scholar
  16. 16.
    Beguin P, Nagashima K, Gonoi T, Shibasaki T, Takahashi K, Kashima Y, Ozaki N, Geering K, Iwanaga T, Seino S: Regulation of Ca2+ channel expression at the cell surface by the small G-protein kir/Gem. Nature 411: 701-706, 2001Google Scholar
  17. 17.
    White RE, Hartzell HC: Effects of intracellular free magnesium on calcium current in isolated cardiac myocytes. Science 239: 778-780, 1988Google Scholar
  18. 18.
    Hartzell HC, White RE: Effects of magnesium on inactivation of the voltage-gated calcium current in cardiac myocytes. J Gen Physiol 94: 745-767, 1989Google Scholar
  19. 19.
    Yamaoka K, Seyama I: Regulation of Ca channel by intracellular Ca2+ and Mg2+ in frog ventricular cells. Pflügers Arch 431: 305-317, 1996Google Scholar
  20. 20.
    Agus ZS, Kelepouris E, Dukes I, Morad M: Cytosolic magnesium modulates calcium channel activity in mammalian ventricular cells. Am J Physiol 256: C452-C455, 1989Google Scholar
  21. 21.
    Backx PH, O'Rourke B, Marban E: Flash photolysis of magnesium-DM-nitrophen in heart cells. A novel approach to probe magnesium-and ATP-dependent regulation of calcium channels. Am J Hypertens 4: 4165-4213, 1991Google Scholar
  22. 22.
    O'Rourke B, Backx PH, Marban E: Phosphorylation-independent modulation of L-type calcium channels by magnesium-nucleotide complexes. Science 257: 245-248, 1992Google Scholar
  23. 23.
    Romanin C, Grosswagen P, Schindler H: Calpastatin and nucleotides stabilize cardiac calcium channel activity in excised patches. Pflügers Arch 418: 86-92, 1991Google Scholar
  24. 24.
    McDonald TF, Pelzer S, Trautwein W, Pelzer DJ: Regulation and modulation of calcium channels in cardiac, skeletal, and smooth muscle cells. Physiol Rev 74: 365-507, 1994Google Scholar
  25. 25.
    Kameyama A, Yazawa K, Kaibara M, Ozono K, Kameyama M: Run-down of the cardiac Ca2+ channel: Characterization and restoration of channel activity by cytoplasmic factors. Pflügers Arch 433: 547-556, 1997Google Scholar
  26. 26.
    Hagiwara S, Byerly L: The calcium channel. Trends Neurosci 6: 189-193, 1983Google Scholar
  27. 27.
    Kostyuk PG: Intracellular perfusion of nerve cells and its effects on membrane currents. Physiol Rev 64: 435-454, 1984Google Scholar
  28. 28.
    Chad JE, Eckert R: An enzymatic mechanism for calcium current inactivation in dialysed Helix neurones. J Physiol (Lond) 378: 31-51, 1986Google Scholar
  29. 29.
    Belles B, Malecot CO, Hescheler J, Trautwein W: 'Run-down' of the Ca current during long whole-cell recordings in guinea pig heart cells: Role of phosphorylation and intracellular calcium. Pflügers Arch 411: 353-360, 1988Google Scholar
  30. 30.
    Kameyama M, Kameyama A, Nakayama T, Kaibara M: Tissue extract recovers cardiac calcium channels from 'run-down'. Pflügers Arch 412: 328-330, 1988Google Scholar
  31. 31.
    Scamps F, Legssyer A, Mayoux E, Vassort G: The mechanism of positive inotropy induced by adenosine triphosphate in rat heart. Circ Res 67: 1007-1016, 1990Google Scholar
  32. 32.
    Qu Y, Campbell DL, Strauss HC: Modulation of L-type Ca2+ current by extracellular ATP in ferret isolated right ventricular myocytes. J Physiol (Lond) 471: 295-317, 1993Google Scholar
  33. 33.
    Scamps F, Vassort G: Pharmacological profile of the ATP-mediated increase in L-type calcium current amplitude and activation of a non-specific cationic current in rat ventricular cells. Br J Pharmacol 113: 982-986, 1994Google Scholar
  34. 34.
    Liu QY, Rosenberg RL: Stimulation of cardiac L-type calcium channels by extracellular ATP. Am J Physiol 280: C1107-C1113, 2001Google Scholar
  35. 35.
    Yazawa K, Kameyama A, Yasui K, Li JM, Kameyama M: ATP regulates cardiac Ca2+ channel activity via a mechanism independent of protein phosphorylation. Pflügers Arch 433: 557-562, 1997Google Scholar
  36. 36.
    Losito VA, Tsushima RG, Diaz RJ, Wilson GJ, Backx PH: Preferential regulation of rabbit cardiac L-type Ca2+ current by glycolytic derived ATP via a direct allosteric pathway. J Physiol (Lond) 511: 67-78, 1998Google Scholar
  37. 37.
    Hao LY, Kameyama A, Kameyama M: A cytoplasmic factor, calpastatin and ATP together reverse run-down of Ca2+ channel activity in guineapig heart. J Physiol (Lond) 514: 687-699, 1999Google Scholar
  38. 38.
    Mubagwa K, Pappano AJ: N-ethylmaleimide increases the L-type calcium current in guinea-pig ventricular myocytes. Arch Int Pharmacodyn Ther 327: 125-141, 1994Google Scholar
  39. 39.
    Campbell DL, Stamler JS, Strauss HC: Redox modulation of L-type calcium channels in ferret ventricular myocytes. Dual mechanism regulation by nitric oxide and S-nitrosothiols. J Gen Physiol 108: 277-293, 1996Google Scholar
  40. 40.
    Lacampagne A, Duittoz A, Bolanos P, Peineau N, Argibay JA: Effect of sulfhydryl oxidation on ionic and gating currents associated with L-type calcium channels in isolated guinca-pig ventricular myocytes. Cardiovasc Res 30: 799-806, 1995Google Scholar
  41. 41.
    Nakajima T, Irisawa H, Giles W: N-ethylmaleimide uncouples muscarinic receptors from acetylcholine-sensitive potassium channels in bullfrog atrium. J Gen Physiol 96: 887-903, 1990Google Scholar
  42. 42.
    Guerra L, Cerbai E, Gessi S, Borea PA, Mugelli A: The effect of oxygen free radicals on calcium current and dihydropyridine binding sites in guinea-pig ventricular myocytes. Br J Pharmacol 118: 1278-1284, 1996Google Scholar
  43. 43.
    Hammerschmidt S, Wahn H: The effect of the oxidant hypochlorous acid on the L-type calcium current in isolated ventricular cardiomyocytes. J Mol Cell Cardiol 30: 1855-1867, 1998Google Scholar
  44. 44.
    Yamaoka K, Yakehiro M, Yuki T, Fujii H, Seyama I: Effect of sulfhydryl reagents on the regulatory system of the L-type Ca channel in frog ventricular myocytes. Pflügers Arch 440: 207-215, 2000Google Scholar
  45. 45.
    Kourie JI: Interaction of reactive oxygen species with ion transport mechanisms. Am J Physiol 275: C1-C24, 1998Google Scholar
  46. 46.
    MacDermott M: The intracellular concentration of free magnesium in extensor digitorum longus muscles of the rat. Exp Physiol 75: 763-769, 1990Google Scholar
  47. 47.
    Hongo K, Konishi M, Kurihara S: Cytoplasmic free Mg2+ in rat ventricular myocytes studied with the fluorescent indicator furaptra. Jpn J Physiol 44: 357-378, 1994Google Scholar
  48. 48.
    Nishimura H, Matsubara T, Ikoma Y, Nakayama S, Sakamoto N: Effects of prolonged application of isoprenaline on intracellular free magnesium concentration in isolated heart of rat. Br J Pharmacol 109: 443-448, 1993Google Scholar
  49. 49.
    Gupta RK, Moore RD: 31P NMR studies of intracellular free Mg2+ in intact frog skeletal muscle. J Biol Chem 255: 3987-3993, 1980Google Scholar
  50. 50.
    Alvarez Leefmans FJ, Gamino SM, Giraldez F, Gonzalez Serratos H: Intracellular free magnesium in frog skeletal muscle fibres measured with ion-selective micro-electrodes. J Physiol (Lond) 378: 461-483, 1986Google Scholar
  51. 51.
    Murphy E, Steenbergen C, Levy LA, Raju B, London RE: Cytosolic free magnesium levels in ischemic rat heart. J Biol Chem 264: 5622-5627, 1989Google Scholar
  52. 52.
    Schachter M, Gallagher KL, Sever PS: Measurement of intracellular magnesium in a vascular smooth muscle cell line using a fluorescent probe. Biochim Biophys Acta 1035: 378-380, 1990Google Scholar
  53. 53.
    Silverman HS, Di Lisa F, Hui RC, Miyata H, Sollott SJ, Hanford RG, Lakatta EG, Stern MD: Regulation of intracellular free Mg2+ and contraction in single adult mammalian cardiac myocytes. Am J Physiol 266: C222-C233, 1994Google Scholar
  54. 54.
    Heaton FW: The determination of ionized magnesium in serum and urine. Clin Chim Acta 15: 139-144, 1967Google Scholar
  55. 55.
    Martindale L, Heaton FW: Magnesium deficiency in the adult rat. Biochem J 92: 119-126, 1964Google Scholar
  56. 56.
    Maclntyre I, Davidsson D: The production of secondary potassium depletion, sodium retention, nephrocalcinosis and hypercalcaemia by magnesium deficiency. Biochem J 70: 456-462, 1958Google Scholar
  57. 57.
    Borchgrevink PC, Bergan AS, Bakoy OE, Jynge P: Magnesium and reperfusion of ischemic rat heart as assessed by 31P-NMR. Am J Physiol 256: H195-H204, 1989Google Scholar
  58. 58.
    Baker PF, Crawford AC: Mobility and transport of magnesium in squid giant axons. J Physiol (Lond) 227: 855-874, 1972Google Scholar
  59. 59.
    Baker PF, Crawford AC: Sodium-dependent transport of magnesium ions in giant axons of Loligo forbesi. J Physiol (Lond) 216: 38P-40P, 1971Google Scholar
  60. 60.
    De Weer P: Axoplasmic free magnesium levels and magnesium extrusion from squid giant axons. J Gen Physiol 68: 159-178, 1976Google Scholar
  61. 61.
    Mullins LJ, Brinley FJ, Spangler SG, Abercrombie RF: Magnesium efflux in dialyzed squid axons. J Gen Physiol 69: 389-400, 1977Google Scholar
  62. 62.
    Gonzalez Serratos H, Rasgado Flores H: Extracellular magnesium-dependent sodium efflux in squid giant axons. Am J Physiol 259: C541-C548, 1990Google Scholar
  63. 63.
    Guther T, Vormann J, Forster R: Regulation of intracellular magnesium by Mg2+ efflux. Biochem Biophys Res Commun 119: 124-131, 1984Google Scholar
  64. 64.
    Feray JC, Garay R: An Na+-stimulated Mg2+-transport system in human red blood cells. Biochim Biophys Acta 856: 76-84, 1986Google Scholar
  65. 65.
    Frenkel EJ, Graziani M, Schatzmann HJ: ATP requirement of the sodium-dependent magnesium extrusion from human red blood cells. J Physiol (Lond) 414: 385-397, 1989Google Scholar
  66. 66.
    Flatman PW, Smith LM: Magnesium transport in ferret red cells. J Physiol (Lond) 431: 11-25, 1990Google Scholar
  67. 67.
    Xu W, Willis JS: Sodium transport through the amiloride-sensitive Na-Mg pathway of hamster red cells. J Membr Biol 141: 277-287, 1994Google Scholar
  68. 68.
    Brocard JB, Rajdev S, Reynolds IJ: Glutamate-induced increases in intracellular free Mg2+ in cultured cortical neurons. Neuron 11: 751-757, 1993Google Scholar
  69. 69.
    Stout AK, Li Smerin Y, Johnson JW, Reynolds IJ: Mechanisms of glutamate-stimulated Mg2+ influx and subsequent Mg2+ efflux in rat forebrain neurones in culture. J Physiol (Lond) 492: 641-657, 1996Google Scholar
  70. 70.
    Gunzel D, Schlue WR: Sodium-magnesium antiport in Retzius neurones of the leech Hirudo medicinalis. J Physiol (Lond) 491: 595-608, 1996Google Scholar
  71. 71.
    Cefaratti C, Romani A, Scarpa A: Characterization of two Mg2+ transporters in sealed plasma membrane vesicles from rat liver. Am J Physiol 275: C995-C1008, 1998Google Scholar
  72. 72.
    Palaty V: Regulation of the cell magnesium in vascular smooth muscle. J Physiol (Lond) 242: 555-569, 1974Google Scholar
  73. 73.
    Shetty SS, Weiss GB: Alterations in 28Mg distribution and movements in rabbit aortic smooth muscle. J Pharmacol Exp Ther 245: 112-119, 1988Google Scholar
  74. 74.
    Nakayama S, Tomita T: Regulation of intracellular free magnesium concentration in the taenia of guinea-pig caecum. J Physiol (Lond) 435: 559-572, 1991Google Scholar
  75. 75.
    Tashiro M, Konishi M: Na+ gradient-dependent Mg2+ transport in smooth muscle cells of guinea pig tenia cecum. Biophys J 73: 3371-3384, 1997Google Scholar
  76. 76.
    Nakayama S, Nomura H, Tomita T: Intracellular-free magnesium in the smooth muscle of guinea pig taenia caeci: A concomitant analysis for magnesium and pH upon sodium removal. J Gen Physiol 103: 833-851, 1994Google Scholar
  77. 77.
    Buri A, Chen S, Fry CH, Illner H, Kickenweiz E, McGuigan JA, Noble D, Powell T, Twist VW: The regulation of intracellular Mg2+ in guinea-pig heart, studied with Mg2+-selective microelectrodes and fluorochromes. Exp Physiol 78: 221-233, 1993Google Scholar
  78. 78.
    Hall SK, Fry CH: The effects of extracellular Mg on excitation of isolated ventricular myocardium from rat, rabbit and ferret. J Physiol (Lond) 429: 24P. 1990Google Scholar
  79. 79.
    Fry CH: Measurement and control of intracellular magnesium ion concentration in guinea pig and ferret ventricular myocardium. Magnesium 5: 306-316, 1986Google Scholar
  80. 80.
    Handy RD, Gow IF, Ellis D, Flatman PW: Na-dependent regulation of intracellular free magnesium concentration in isolated rat ventricular myocytes. J Mol Cell Cardiol 28: 1641-1651, 1996Google Scholar
  81. 81.
    Romani A, Marfella C, Scarpa A: Regulation of magnesium uptake and release in the heart and in isolated ventricular myocytes. Circ Res 72: 1139-1148, 1993Google Scholar
  82. 82.
    Romani A, Scarpa A: Hormonal control of Mg2+ transport in the heart. Nature 346: 841-844, 1990Google Scholar
  83. 83.
    Vormann J, Gunther T: Amiloride-sensitive net Mg2+ efflux from isolated perfused rat hearts. Magnesium 6: 220-224, 1987Google Scholar
  84. 84.
    Watanabe J, Nakayama S, Matsubara T, Hotta N: Regulation of intracellular free Mg2+ concentration in isolated rat hearts via beta-adrenergic and muscarinic receptors. J Mol Cell Cardiol 30: 2307-2318, 1998Google Scholar
  85. 85.
    Buri A, McGuigan JA: Intracellular free magnesium and its regulation, studied in isolated ferret ventricular muscle with ion-selective microelectrodes. Exp Physiol 75: 751-761, 1990Google Scholar
  86. 86.
    Howarth FC, Levi AJ: Internal free magnesium modulates the voltage dependence of contraction and Ca transient in rabbit ventricular myocytes. Pflügers Arch 435: 687-698, 1998Google Scholar
  87. 87.
    Yamaoka K, Seyama I: Modulation of Ca2+ channels by intracellular Mg2+ ions and GTP in frog ventricular myocytes. Pflügers Arch 432: 433-438, 1996Google Scholar
  88. 88.
    Yamaoka K, Yuki T, Kawase K, Munemori M, Seyama I: Temperature-sensitive intracellular Mg2+ block of L-type Ca2+ channels in cardiac myocytes. Am J Physiol 282: H1092-H1101, 2002Google Scholar
  89. 89.
    Gunther T: Biochemistry and pathobiochemistry of magnesium. Artery 9: 167-181, 1981Google Scholar
  90. 90.
    Ligeti E, Horvath LI: Effect of Mg2+ on membrane fluidity and K+ transport in rat liver mitochondria. Biochim Biophys Acta 600: 150-156, 1980Google Scholar
  91. 91.
    Storch J, Schachter D: Calcium alters the acyl chain composition and lipid fluidity of rat hepatocyte plasma membranes in vitro. Biochim Biophys Acta 812: 473-484, 1985Google Scholar
  92. 92.
    Pelzer S, La C, Pelzer D: Phosphorylation-dependent modulation of cardiac calcium current by intracellular free magnesium. Am J Physiol 281: H1532-H1544, 2001Google Scholar
  93. 93.
    Frace AM, Hartzell HC: Opposite effects of phosphatase inhibitors on L-type calcium and delayed rectifier currents in frog cardiac myocytes. J Physiol (Lond) 472: 305-326, 1993Google Scholar
  94. 94.
    Tsien RW, Bean BP, Hess P, Lansman JB, Nilius B, Nowycky MC: Mcchanisms of calcium channel modulation by β-adrenergic agents and dihydropyridine calcium agonists. J Mol Cell Cardiol 18: 691-710, 1986Google Scholar
  95. 95.
    Ochi R, Kawashima Y: Modulation of slow gating process of calcium channels by isoprenaline in guinea-pig ventricular cells. J Physiol (Lond) 424: 187-204, 1990Google Scholar
  96. 96.
    Rose WC, Balke CW, Wier WG, Marban E: Macroscopic and unitary properties of physiological ion flux through L-type Ca2+ channels in guinea-pig heart cells. J Physiol (Lond) 456: 267-284, 1992Google Scholar
  97. 97.
    Ono K, Fozzard HA: Two phosphatase sites on the Ca2+ channel affecting different kinetic functions. J Physiol (Lond) 470: 73-84, 1993Google Scholar
  98. 98.
    Brum G, Osterrieder W, Trautwein W: β-adrenergic increase in the calcium conductance of cardiac myocytes studied with the patch clamp. Pflügers Arch 401: 111-118, 1984Google Scholar
  99. 99.
    Cachelin AB, de Peyer JE, Kokubun S, Reuter H: Ca2+ channel modulation by 8-bromocyclic AMP in cultured heart cells. Nature 304: 462-464, 1983Google Scholar
  100. 100.
    Hess P, Lansman JB, Tsien RW: Different modes of Ca channel gating behaviour favoured by dihydropyridine Ca agonists and antagonists. Nature 311: 538-544, 1984Google Scholar
  101. 101.
    Wiechen K, Yue DT, Herzig S: Two distinct functional effects of protein phosphatase inhibitors on guinea-pig cardiac L-type Ca2+ channels. J Physiol (Lond) 484: 583-592, 1995Google Scholar
  102. 102.
    Catterall WA: Structure and function of voltage-sensitive ion channels. Science 242: 50-61, 1988Google Scholar
  103. 103.
    Catterall WA: Structure and regulation of voltage-gated Ca2+ channels. Ann Rev Cell Dev Biol 16: 521-555, 2000Google Scholar
  104. 104.
    Hell JW, Yokoyama CT, Wong ST, Warner C, Snutch TP, Catterall WA: Differential phosphorylation of two size forms of the neuronal class CL-type calcium channel a1 subunit. J Biol Chem 268: 19451-19457, 1993Google Scholar
  105. 105.
    De Jongh KS, Murphy BJ, Colvin AA, Hell JW, Takahashi M, Catterall WA: Specific phosphorylation of a site in the full-length form of the α1 subunit of the cardiac L-type calcium channel by adenosine 3′,5′-cyclic monophosphate-dependent protein kinase. Biochemistry 35: 10392-10402, 1996Google Scholar
  106. 106.
    Perets T, Blumenstein Y, Shistik E, Lotan I, Dascal N: A potential site of functional modulation by protein kinase A in the cardiac Ca2+ channel α1C subunit. FEBS Lett 384: 189-192, 1996Google Scholar
  107. 107.
    Mitterdorfer J, Froschmayr M, Grabner M, Moebius FF, Glossmann H, Striessnig J: Identification of PK-A phosphorylation sites in the carboxyl terminus of L-type calcium channel α1 subunits. Biochemistry 35: 9400-9406, 1996Google Scholar
  108. 108.
    Naguro I, Nagao T, Adachi-Akahane S: Ser1901 of α1C subunit is required for the PKA-mediated enhancement of L-type Ca2+ channel currents but not for the negative shift of activation. FEBS Lett 489: 87-91, 2001Google Scholar
  109. 109.
    Haase H, Bartel S, Karczewski P, Morano I, Krause EG: In vivo phosphorylation of the cardiac L-type calcium channel β-subunit in response to catecholamines. Mol Cell Biochem 163-164: 99-106, 1996Google Scholar
  110. 110.
    Puri TS, Gerhardstein BL, Zhao XL, Ladner MB, Hosey MM: Differential effects of subunit interactions on protein kinase A-and C-mediated phosphorylation of L-type calcium channels. Biochemistry 36: 9605-9615, 1997Google Scholar
  111. 111.
    Gerhardstein BL, Puri TS, Chien AJ, Hosey MM: Identification of the sites phosphorylated by cyclic AMP-dependent protein kinase on the β2 subunit of L-type voltage-dependent calcium channels. Biochemistry 38: 10361-10370, 1999Google Scholar
  112. 112.
    Xiao RP, Cheng H, Zhou YY, Kuschel M, Lakatta EG: Recent advances in cardiac β2-adrenergic signal transduction. Circ Res 85: 1092-1100, 1999Google Scholar
  113. 113.
    Rybin VO, Xu X, Steinberg SF: Activated protein kinase C isoforms target to cardiomyocyte caveolae: Stimulation of local protein phosphorylation. Circ Res 84: 980-988, 1999Google Scholar
  114. 114.
    Armstrong D, Eckert R: Voltage-activated calcium channels that must be phosphorylated to respond to membrane depolarization. Proc Natl Acad Sci USA 84: 2518-2522, 1987Google Scholar
  115. 115.
    Schneider JA, Sperelakis N: The demonstration of energy dependence of the isoproterenol-induced transcellular Ca2+ current in isolated perfused guinea pig hearts — an explanation for mechanical failure of ischemic myocardium. J Surg Res 16: 389-403, 1974Google Scholar
  116. 116.
    Irisawa H, Kokubun S: Modulation by intracellular ATP and cyclic AMP of the slow inward current in isolated single ventricular cells of the guinea-pig. J Physiol (Lond) 338: 321-337, 1983Google Scholar
  117. 117.
    Hescheler J, Kameyama M, Trautwein W: On the mechanism of muscarinic inhibition of the cardiac Ca current. Pflügers Arch 407: 182-189, 1986Google Scholar
  118. 118.
    Hescheler J, Kameyama M, Trautwein W, Mieskes G, Soling HD: Regulation of the cardiac calcium channel by protein phosphatases. Eur J Biochem 165: 261-266, 1987Google Scholar
  119. 119.
    Kameyama M, Hescheler J, Hofmann F, Trautwein W: Modulation of Ca current during the phosphorylation cycle in the guinea pig heart. Pflügers Arch 407: 123-128, 1986Google Scholar
  120. 120.
    Kameyama M, Hescheler J, Mieskes G, Trautwein W: The protein-specific phosphatase 1 antagonizes the β-adrenergic increase of the cardiac Ca current. Pflügers Arch 407: 461-463, 1986Google Scholar
  121. 121.
    Xiao RP, Cheng H, Lederer WJ, Suzuki T, Lakatta EG: Dual regulation of Ca2+/calmodulin-dependent kinase II activity by membrane voltage and by calcium influx. Proc Natl Acad Sci USA 91: 9659-9663, 1994Google Scholar
  122. 122.
    Vinogradova TM, Zhou YY, Bogdanov KY, Yang D, Kuschel M, Cheng H, Xiao RP: Sinoatrial node pacemaker activity requires Ca2+/calmodulin-dependent protein kinase II activation. Circ Res 87: 760-767, 2000Google Scholar
  123. 123.
    Ono K, Fozzard HA: Phosphorylation restores activity of L-type calcium channels after rundown in inside-out patches from rabbit cardiac cells. J Physiol (Lond) 454: 673-688, 1992Google Scholar
  124. 124.
    Yatani A, Codina J, Imoto Y, Reeves JP, Birnbaumer L, Brown AM: A G protein directly regulates mammalian cardiac calcium channels. Science 238: 1288-1292, 1987Google Scholar
  125. 125.
    Costantin JL, Qin N, Waxham MN, Birnbaumer L, Stefani E: Complete reversal of run-down in rabbit cardiac Ca2+ channels by patch-cramming in Xenopus oocytes; partial reversal by protein kinase A. Pflügers Arch 437: 888-894, 1999Google Scholar
  126. 126.
    Melloni E, Salamino F, Sparatore B: The calpain-calpastatin system in mammalian cells: Properties and possible functions. Biochimie 74: 217-223, 1992Google Scholar
  127. 127.
    Murachi T: Intracellular regulatory system involving calpain and calpastatin. Biochem Int 18: 263-294, 1989Google Scholar
  128. 128.
    Suzuki K, Imajoh S, Emori Y, Kawasaki H, Minami Y, Ohno S: Regulation of activity of calcium activated neutral protease. Adv Enzyme Regul 27: 153-169, 1988Google Scholar
  129. 129.
    Asada K, Ishino Y, Shimada M, Shimojo T, Endo M, Kimizuka F, Kato I, Maki M, Hatanaka M, Murachi T: cDNA cloning of human calpastatin: Sequence homology among human, pig, and rabbit calpastatins. J Enzym Inhib 3: 49-56, 1989Google Scholar
  130. 130.
    Emori Y, Kawasaki H, Imajoh S, Imahori K, Suzuki K: Endogenous inhibitor for calcium-dependent cysteine protease contains four internal repeats that could be responsible for its multiple reactive sites. Proc Natl Acad Sci USA 84: 3590-3594, 1987Google Scholar
  131. 131.
    Takano E, Maki M, Mori H, Hatanaka M, Marti T, Titani K, Kannagi R, Ooi T, Murachi T: Pig heart calpastatin: Identification of repetitive domain structures and anomalous behavior in polyacrylamide gel electrophoresis. Biochemistry 27: 1964-1972, 1988Google Scholar
  132. 132.
    Imajoh S, Kawasaki H, Emori Y, Suzuki K: Calcium-activated neutral protease inhibitor from rabbit erythrocytes lacks the N-terminal region of the liver inhibitor but retains three inhibitory units. Biochem Biophys Res Commun 146: 630-637, 1987Google Scholar
  133. 133.
    Kamcyama A, Hao LY, Takano E, Kameyama M: Characterization and partial purification of the cytoplasmic factor that maintains cardiac Ca2+ channel activity. Pflügers Arch 435: 338-343, 1998Google Scholar
  134. 134.
    Kameyama M, Kameyama A, Takano E, Maki M: Run-down of the cardiac L-type Ca2+ channel: partial restoration of channel activity in cell-free patches by calpastatin. Pflügers Arch 435: 344-349, 1998Google Scholar
  135. 135.
    Seydl K, Karlsson JO, Dominik A, Gruber H, Romanin C: Action of calpastatin in prevention of cardiac L-type Ca2+ channel run-down cannot be mimicked by synthetic calpain inhibitors. Pflügers Arch 429: 503-510, 1995Google Scholar
  136. 136.
    Hao LY, Kameyama A, Kuroki S, Takano J, Takano E, Maki M, Kameyama M: Calpastatin domain L is involved in the regulation of L-type Ca2+ channels in guinea pig cardiac myocytes. Biochem Biophys Res Commun 279: 756-761, 2000Google Scholar
  137. 137.
    Hao LY, Kameyama A, Kuroki S, Nishimura S, Kameyama M: Rundown of L-type Ca2+ channels occurs on the α1 subunit. Biochem Biophys Res Commun 247: 844-850, 1998Google Scholar
  138. 138.
    Noma A, Shibasaki T: Membrane current through adenosine-triphosphate-regulated potassium channels in guinca-pig ventricular cells. J Physiol (Lond) 363: 463-480, 1985Google Scholar
  139. 139.
    Osterrieder W, Brum G, Hescheler J, Trautwein W, Flockerzi V, Hofmann F: Injection of subunits of cyclic AMP-dependent protein kinase into cardiac myocytes modulates Ca2+ current. Nature 298: 576-578, 1982Google Scholar
  140. 140.
    Kameyama M, Hofmann F, Trautwein W: On the mechanism of β-adrenergic regulation of the Ca channel in the guinca-pig heart. Pflügers Arch 405: 285-293, 1985Google Scholar
  141. 141.
    Reuter H: Calcium channel modulation by neurotransmitters, enzymes and drugs. Nature 301: 569-574, 1983Google Scholar
  142. 142.
    Drummond GI, Severson DL: Cyclic nucleotides and cardiac function. Circ Res 44: 145-153, 1979Google Scholar
  143. 143.
    Tsien RW: Cyclic AMP and contractile activity in heart. Adv Cyclic Nucleotide Res 8: 363-420, 1977Google Scholar
  144. 144.
    Kokubun S, Irisawa H: Effects of various intracellular Ca ion concentrations on the calcium current of guinea-pig single ventricular cells. Jpn J Physiol 34: 599-611, 1984Google Scholar
  145. 145.
    Romanin C, Karlsson JO, Schindler H: Activity of cardiac L-type Ca2+ channels is sensitive to cytoplasmic calcium. Pflügers Arch 421: 516-518, 1992Google Scholar
  146. 146.
    Brown AM, Morimoto K, Tsuda Y, Wilson DL: Calcium current-dependent and voltage-dependent inactivation of calcium channels in Helix aspersa. J Physiol (Lond) 320: 193-218, 1981Google Scholar
  147. 147.
    Eckert R, Tillotson DL: Calcium-mediated inactivation of the calcium conductance in caesium-loaded giant neurones of Aplysia californica. J Physiol (Lond) 314: 265-280, 1981Google Scholar
  148. 148.
    Belles B, Hescheler J, Trautwein W, Blomgren K, Karlsson JO: A possible physiological role of the Ca-dependent protease calpain and its inhibitor calpastatin on the Ca current in guinea pig myocytes. Pflügers Arch 412: 554-556, 1988Google Scholar
  149. 149.
    Blatter LA, McGuigan JAS: Free intracellular magnesium concentration in ferret ventricular muscle measured with ion selective microelectrodes. Q J Exp Physiol 71: 467-473, 1986Google Scholar
  150. 150.
    Lory P, Nargeot J: Cyclic AMP-dependent modulation of cardiac Ca channels expressed in Xenopus laevis oocytes. Biochem Biophys Res Commun 182: 1059-1065, 1992Google Scholar
  151. 151.
    Dascal N, Snutch TP, Lubbert H, Davidson N, Lester HA: Expression and modulation of voltage-gated calcium channels after RNA injection in Xenopus oocytes. Science 231: 1147-1150, 1986Google Scholar
  152. 152.
    Klöckner U, Itagaki K, Bodi I, Schwartz A: β-Subunit expression is required for cAMP-dependent increase of cloned cardiac and vascular calcium channel currents. Pflügers Arch 420: 413-415, 1992Google Scholar
  153. 153.
    Singer Lahat D, Lotan I, Biel M, Flockerzi V, Hofmann F, Dascal N: Cardiac calcium channels expressed in Xenopus oocytes are modulated by dephosphorylation but not by cAMP-dependent phosphorylation. Receptors Channels 2: 215-226, 1994Google Scholar
  154. 154.
    Zong X, Schreieck J, Mehrke G, Welling A, Schuster A, Bosse E, Flockerzi V, Hofmann F: On the regulation of the expressed L-type calcium channel by cAMP-dependent phosphorylation. Pflügers Arch 430: 340-347, 1995Google Scholar
  155. 155.
    Yoshida A, Takahashi M, Nishimura S, Takeshima H, Kokubun S: Cyclic AMP-dependent phosphorylation and regulation of the cardiac dihydropyridine-sensitive Ca channel. FEBS Lett 309: 343-349, 1992Google Scholar
  156. 156.
    Perez Reyes E, Yuan W, Wei X, Bers DM: Regulation of the cloned L-type cardiac calcium channel by cyclic-AMP-dependent protein kinase. FEBS Lett 342: 119-123, 1994Google Scholar
  157. 157.
    Hirano Y, Yoshinaga T, Niidome T, Katayama K, Hiraoka M: Modulation by dihydropyridines and protein kinases of the recombinant cardiac L-type Ca channel with multiple unitary current amplitudes. Receptors Channels 4: 93-104, 1996Google Scholar

Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  • Kaoru Yamaoka
    • 1
  • Masaki Kameyama
    • 2
  1. 1.Department of Physiology, School of MedicineHiroshima UniversityMinami-Ku, HiroshimaJapan
  2. 2.Department of Physiology, Faculty of MedicineKagoshima UniversitySakura-ga-oka, KagoshimaJapan

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