Ryanodine receptor channelopathies

  • Matthew J. Betzenhauser
  • Andrew R. MarksEmail author
Invited Review


Ryanodine receptors (RyR) are intracellular Ca2+-permeable channels that provide the sarcoplasmic reticulum Ca2+ release required for skeletal and cardiac muscle contractions. RyR1 underlies skeletal muscle contraction, and RyR2 fulfills this role in cardiac muscle. Over the past 20 years, numerous mutations in both RyR isoforms have been identified and linked to skeletal and cardiac diseases. Malignant hyperthermia, central core disease, and catecholaminergic polymorphic ventricular tachycardia have been genetically linked to mutations in either RyR1 or RyR2. Thus, RyR channelopathies are both of interest because they cause significant human diseases and provide model systems that can be studied to elucidate important structure–function relationships of these ion channels.


Ryanodine receptors Calcium-induced calcium release Muscle contraction Arrhythmias Mutation 



Dr. Marks is a consultant for ARMGO Pharma, Inc, a start-up company targeting RyR2 to treat HF and cardiac arrhythmias, and is the recipient of funding from the National Institutes of Health (HL 061503, HL 067849, HL 056180, and HL 083418) and from the Fondation Leducq.


  1. 1.
    Amador FJ, Liu S, Ishiyama N, Plevin MJ, Wilson A, MacLennan DH, Ikura M (2009) Crystal structure of type I ryanodine receptor amino-terminal beta-trefoil domain reveals a disease-associated mutation “hot spot” loop. Proc Natl Acad Sci U S A 106:11040–11044PubMedCrossRefGoogle Scholar
  2. 2.
    Andronache Z, Hamilton SL, Dirksen RT, Melzer W (2009) A retrograde signal from RyR1 alters DHP receptor inactivation and limits window Ca2+ release in muscle fibers of Y522S RyR1 knock-in mice. Proc Natl Acad Sci U S A 106:4531–4536PubMedCrossRefGoogle Scholar
  3. 3.
    Avila G, Dirksen RT (2001) Functional effects of central core disease mutations in the cytoplasmic region of the skeletal muscle ryanodine receptor. J Gen Physiol 118:277–290PubMedCrossRefGoogle Scholar
  4. 4.
    Avila G, O'Brien JJ, Dirksen RT (2001) Excitation–contraction uncoupling by a human central core disease mutation in the ryanodine receptor. Proc Natl Acad Sci U S A 98:4215–4220PubMedCrossRefGoogle Scholar
  5. 5.
    Balschun D, Wolfer DP, Bertocchini F, Barone V, Conti A, Zuschratter W, Missiaen L, Lipp HP, Frey JU, Sorrentino V (1999) Deletion of the ryanodine receptor type 3 (RyR3) impairs forms of synaptic plasticity and spatial learning. EMBO J 18:5264–5273PubMedCrossRefGoogle Scholar
  6. 6.
    Balshaw DM, Xu L, Yamaguchi N, Pasek DA, Meissner G (2001) Calmodulin binding and inhibition of cardiac muscle calcium release channel (ryanodine receptor). J Biol Chem 276:20144–20153PubMedCrossRefGoogle Scholar
  7. 7.
    Bellinger AM, Mongillo M, Marks AR (2008) Stressed out: the skeletal muscle ryanodine receptor as a target of stress. J Clin Invest 118:445–453PubMedCrossRefGoogle Scholar
  8. 8.
    Bellinger AM, Reiken S, Carlson C, Mongillo M, Liu X, Rothman L, Matecki S, Lacampagne A, Marks AR (2009) Hypernitrosylated ryanodine receptor calcium release channels are leaky in dystrophic muscle. Nat Med 15:325–330PubMedCrossRefGoogle Scholar
  9. 9.
    Bellinger AM, Reiken S, Dura M, Murphy PW, Deng SX, Landry DW, Nieman D, Lehnart SE, Samaru M, LaCampagne A, Marks AR (2008) Remodeling of ryanodine receptor complex causes “leaky” channels: a molecular mechanism for decreased exercise capacity. Proc Natl Acad Sci U S A 105:2198–2202PubMedCrossRefGoogle Scholar
  10. 10.
    Berridge MJ, Lipp P, Bootman MD (2000) The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol 1:11–21PubMedCrossRefGoogle Scholar
  11. 11.
    Bers DM (2002) Cardiac excitation–contraction coupling. Nature 415:198–205PubMedCrossRefGoogle Scholar
  12. 12.
    Brillantes AB, Ondrias K, Scott A, Kobrinsky E, Ondriasova E, Moschella MC, Jayaraman T, Landers M, Ehrlich BE, Marks AR (1994) Stabilization of calcium release channel (ryanodine receptor) function by FK506-binding protein. Cell 77:513–523PubMedCrossRefGoogle Scholar
  13. 13.
    Bristow MR, Ginsburg R, Minobe W, Cubicciotti RS, Sageman WS, Lurie K, Billingham ME, Harrison DC, Stinson EB (1982) Decreased catecholamine sensitivity and beta-adrenergic-receptor density in failing human hearts. N Engl J Med 307:205–211PubMedCrossRefGoogle Scholar
  14. 14.
    Britt BA, Kalow W (1970) Malignant hyperthermia: a statistical review. Can Anaesth Soc J 17:293–315PubMedCrossRefGoogle Scholar
  15. 15.
    Callewaert G, Cleemann L, Morad M (1988) Epinephrine enhances Ca2+ current-regulated Ca2+ release and Ca2+ reuptake in rat ventricular myocytes. Proc Natl Acad Sci U S A 85:2009–2013PubMedCrossRefGoogle Scholar
  16. 16.
    Cerrone M, Colombi B, Santoro M, di Barletta MR, Scelsi M, Villani L, Napolitano C, Priori SG (2005) Bidirectional ventricular tachycardia and fibrillation elicited in a knock-in mouse model carrier of a mutation in the cardiac ryanodine receptor. Circ Res 96:e77–e82PubMedCrossRefGoogle Scholar
  17. 17.
    Cerrone M, Napolitano C, Priori SG (2009) Catecholaminergic polymorphic ventricular tachycardia: a paradigm to understand mechanisms of arrhythmias associated to impaired Ca(2+) regulation. Heart Rhythm 6:1652–1659PubMedCrossRefGoogle Scholar
  18. 18.
    Cerrone M, Noujaim SF, Tolkacheva EG, Talkachou A, O'Connell R, Berenfeld O, Anumonwo J, Pandit SV, Vikstrom K, Napolitano C, Priori SG, Jalife J (2007) Arrhythmogenic mechanisms in a mouse model of catecholaminergic polymorphic ventricular tachycardia. Circ Res 101:1039–1048PubMedCrossRefGoogle Scholar
  19. 19.
    Chakroborty S, Goussakov I, Miller MB, Stutzmann GE (2009) Deviant ryanodine receptor-mediated calcium release resets synaptic homeostasis in presymptomatic 3xTg-AD mice. J Neurosci 29:9458–9470PubMedCrossRefGoogle Scholar
  20. 20.
    Chelu MG, Goonasekera SA, Durham WJ, Tang W, Lueck JD, Riehl J, Pessah IN, Zhang P, Bhattacharjee MB, Dirksen RT, Hamilton SL (2006) Heat- and anesthesia-induced malignant hyperthermia in an RyR1 knock-in mouse. FASEB J 20:329–330PubMedGoogle Scholar
  21. 21.
    Chopra N, Kannankeril PJ, Yang T, Hlaing T, Holinstat I, Ettensohn K, Pfeifer K, Akin B, Jones LR, Franzini-Armstrong C, Knollmann BC (2007) Modest reductions of cardiac calsequestrin increase sarcoplasmic reticulum Ca2+ leak independent of luminal Ca2+ and trigger ventricular arrhythmias in mice. Circ Res 101:617–626PubMedCrossRefGoogle Scholar
  22. 22.
    Clapham DE (2007) Calcium signaling. Cell 131:1047–1058PubMedCrossRefGoogle Scholar
  23. 23.
    De Jongh KS, Murphy BJ, Colvin AA, Hell JW, Takahashi M, Catterall WA (1996) Specific phosphorylation of a site in the full-length form of the alpha 1 subunit of the cardiac L-type calcium channel by adenosine 3′, 5′-cyclic monophosphate-dependent protein kinase. Biochemistry 35:10392–10402PubMedCrossRefGoogle Scholar
  24. 24.
    Denborough MA (2008) Malignant hyperthermia. 1962. Anesthesiology 108:156–157PubMedCrossRefGoogle Scholar
  25. 25.
    Denborough MA, Lovell RRH (1960) Anaesthetic deaths in a family. Lancet 276:45CrossRefGoogle Scholar
  26. 26.
    Dirksen RT, Avila G (2002) Altered ryanodine receptor function in central core disease: leaky or uncoupled Ca(2+) release channels? Trends Cardiovasc Med 12:189–197PubMedCrossRefGoogle Scholar
  27. 27.
    Dirksen RT, Avila G (2004) Distinct effects on Ca2+ handling caused by malignant hyperthermia and central core disease mutations in RyR1. Biophys J 87:3193–3204PubMedCrossRefGoogle Scholar
  28. 28.
    Du GG, Sandhu B, Khanna VK, Guo XH, MacLennan DH (2002) Topology of the Ca2+ release channel of skeletal muscle sarcoplasmic reticulum (RyR1). Proc Natl Acad Sci U S A 99:16725–16730PubMedCrossRefGoogle Scholar
  29. 29.
    Durham WJ, Aracena-Parks P, Long C, Rossi AE, Goonasekera SA, Boncompagni S, Galvan DL, Gilman CP, Baker MR, Shirokova N, Protasi F, Dirksen R, Hamilton SL (2008) RyR1 S-nitrosylation underlies environmental heat stroke and sudden death in Y522S RyR1 knock in mice. Cell 133:53–65PubMedCrossRefGoogle Scholar
  30. 30.
    Ehrlich BE, Kaftan E, Bezprozvannaya S, Bezprozvanny I (1994) The pharmacology of intracellular Ca(2+)-release channels. Trends Pharmacol Sci 15:145–149PubMedCrossRefGoogle Scholar
  31. 31.
    Ellis FR, Harriman DG (1973) A new screening test for susceptibility to malignant hyperpyrexia. Br J Anaesth 45:638PubMedCrossRefGoogle Scholar
  32. 32.
    Eu JP, Sun J, Xu L, Stamler JS, Meissner G (2000) The skeletal muscle calcium release channel: coupled O2 sensor and NO signaling functions. Cell 102:499–509PubMedCrossRefGoogle Scholar
  33. 33.
    Fauconnier J, Thireau J, Reiken S, Cassan C, Richard S, Matecki S, Marks AR, Lacampagne A (2010) Leaky RyR2 trigger ventricular arrhythmias in Duchenne muscular dystrophy. Proc Natl Acad Sci U S A 107:1559–1564PubMedCrossRefGoogle Scholar
  34. 34.
    Fill M, Copello JA (2002) Ryanodine receptor calcium release channels. Physiol Rev 82:893–922PubMedGoogle Scholar
  35. 35.
    Fill M, Coronado R, Mickelson JR, Vilven J, Ma JJ, Jacobson BA, Louis CF (1990) Abnormal ryanodine receptor channels in malignant hyperthermia. Biophys J 57:471–475PubMedCrossRefGoogle Scholar
  36. 36.
    Fill M, Stefani E, Nelson TE (1991) Abnormal human sarcoplasmic reticulum Ca2+ release channels in malignant hyperthermic skeletal muscle. Biophys J 59:1085–1090PubMedCrossRefGoogle Scholar
  37. 37.
    Fleischer S, Ogunbunmi EM, Dixon MC, Fleer EA (1985) Localization of Ca2+ release channels with ryanodine in junctional terminal cisternae of sarcoplasmic reticulum of fast skeletal muscle. Proc Natl Acad Sci U S A 82:7256–7259PubMedCrossRefGoogle Scholar
  38. 38.
    Fozzard HA (1992) Afterdepolarizations and triggered activity. Basic Res Cardiol 87(Suppl 2):105–113PubMedGoogle Scholar
  39. 39.
    Fujii J, Otsu K, Zorzato F, de Leon S, Khanna VK, Weiler JE, O'Brien PJ, MacLennan DH (1991) Identification of a mutation in porcine ryanodine receptor associated with malignant hyperthermia. Science 253:448–451PubMedCrossRefGoogle Scholar
  40. 40.
    Gellen B, Fernandez-Velasco M, Briec F, Vinet L, LeQuang K, Rouet-Benzineb P, Benitah JP, Pezet M, Palais G, Pellegrin N, Zhang A, Perrier R, Escoubet B, Marniquet X, Richard S, Jaisser F, Gomez AM, Charpentier F, Mercadier JJ (2008) Conditional FKBP12.6 overexpression in mouse cardiac myocytes prevents triggered ventricular tachycardia through specific alterations in excitation–contraction coupling. Circulation 117:1778–1786PubMedCrossRefGoogle Scholar
  41. 41.
    George CH, Higgs GV, Lai FA (2003) Ryanodine receptor mutations associated with stress-induced ventricular tachycardia mediate increased calcium release in stimulated cardiomyocytes. Circ Res 93:531–540PubMedCrossRefGoogle Scholar
  42. 42.
    George CH, Jundi H, Thomas NL, Fry DL, Lai FA (2007) Ryanodine receptors and ventricular arrhythmias: emerging trends in mutations, mechanisms and therapies. J Mol Cell Cardiol 42:34–50PubMedCrossRefGoogle Scholar
  43. 43.
    George CH, Jundi H, Walters N, Thomas NL, West RR, Lai FA (2006) Arrhythmogenic mutation-linked defects in ryanodine receptor autoregulation reveal a novel mechanism of Ca2+ release channel dysfunction. Circ Res 98:88–97PubMedCrossRefGoogle Scholar
  44. 44.
    Gillard EF, Otsu K, Fujii J, Khanna VK, de Leon S, Derdemezi J, Britt BA, Duff CL, Worton RG, MacLennan DH (1991) A substitution of cysteine for arginine 614 in the ryanodine receptor is potentially causative of human malignant hyperthermia. Genomics 11:751–755PubMedCrossRefGoogle Scholar
  45. 45.
    Goddard CA, Ghais NS, Zhang Y, Williams AJ, Colledge WH, Grace AA, Huang CL (2008) Physiological consequences of the P2328S mutation in the ryanodine receptor (RyR2) gene in genetically modified murine hearts. Acta Physiol (Oxf) 194:123–140CrossRefGoogle Scholar
  46. 46.
    Harrison GG (1975) Control of the malignant hyperpyrexic syndrome in MHS swine by dantrolene sodium. Br J Anaesth 47:62–65PubMedCrossRefGoogle Scholar
  47. 47.
    Huang F, Shan J, Reiken S, Wehrens XH, Marks AR (2006) Analysis of calstabin2 (FKBP12.6)–ryanodine receptor interactions: rescue of heart failure by calstabin2 in mice. Proc Natl Acad Sci U S A 103:3456–3461PubMedCrossRefGoogle Scholar
  48. 48.
    Hunt DJ, Jones PP, Wang R, Chen W, Bolstad J, Chen K, Shimoni Y, Chen SR (2007) K201 (JTV519) suppresses spontaneous Ca2+ release and [3H]ryanodine binding to RyR2 irrespective of FKBP12.6 association. Biochem J 404:431–438PubMedCrossRefGoogle Scholar
  49. 49.
    Hymel L, Inui M, Fleischer S, Schindler H (1988) Purified ryanodine receptor of skeletal muscle sarcoplasmic reticulum forms Ca2 + -activated oligomeric Ca2+ channels in planar bilayers. Proc Natl Acad Sci U S A 85:441–445PubMedCrossRefGoogle Scholar
  50. 50.
    Jiang MT, Lokuta AJ, Farrell EF, Wolff MR, Haworth RA, Valdivia HH (2002) Abnormal Ca2+ release, but normal ryanodine receptors, in canine and human heart failure. Circ Res 91:1015–1022PubMedCrossRefGoogle Scholar
  51. 51.
    Jiang D, Wang R, Xiao B, Kong H, Hunt DJ, Choi P, Zhang L, Chen SR (2005) Enhanced store overload-induced Ca2+ release and channel sensitivity to luminal Ca2+ activation are common defects of RyR2 mutations linked to ventricular tachycardia and sudden death. Circ Res 97:1173–1181PubMedCrossRefGoogle Scholar
  52. 52.
    Jiang D, Xiao B, Yang D, Wang R, Choi P, Zhang L, Cheng H, Chen SR (2004) RyR2 mutations linked to ventricular tachycardia and sudden death reduce the threshold for store-overload-induced Ca2+ release (SOICR). Proc Natl Acad Sci U S A 101:13062–13067PubMedCrossRefGoogle Scholar
  53. 53.
    Jiang D, Xiao B, Zhang L, Chen SR (2002) Enhanced basal activity of a cardiac Ca2+ release channel (ryanodine receptor) mutant associated with ventricular tachycardia and sudden death. Circ Res 91:218–225PubMedCrossRefGoogle Scholar
  54. 54.
    Jungbluth H, Sewry CA, Muntoni F (2003) What's new in neuromuscular disorders? The congenital myopathies. Eur J Paediatr Neurol 7:23–30PubMedCrossRefGoogle Scholar
  55. 55.
    Kalow W, Britt BA, Terreau ME, Haist C (1970) Metabolic error of muscle metabolism after recovery from malignant hyperthermia. Lancet 2:895–898PubMedCrossRefGoogle Scholar
  56. 56.
    Kaneko N, Matsuda R, Hata Y, Shimamoto K (2009) Pharmacological characteristics and clinical applications of K201. Curr Clin Pharmacol 4:126–131PubMedCrossRefGoogle Scholar
  57. 57.
    Kannankeril PJ, Mitchell BM, Goonasekera SA, Chelu MG, Zhang W, Sood S, Kearney DL, Danila CI, De Biasi M, Wehrens XH, Pautler RG, Roden DM, Taffet GE, Dirksen RT, Anderson ME, Hamilton SL (2006) Mice with the R176Q cardiac ryanodine receptor mutation exhibit catecholamine-induced ventricular tachycardia and cardiomyopathy. Proc Natl Acad Sci U S A 103:12179–12184PubMedCrossRefGoogle Scholar
  58. 58.
    Koulen P, Thrower EC (2001) Pharmacological modulation of intracellular Ca(2+) channels at the single-channel level. Mol Neurobiol 24:65–86PubMedCrossRefGoogle Scholar
  59. 59.
    Kranias EG, Garvey JL, Srivastava RD, Solaro RJ (1985) Phosphorylation and functional modifications of sarcoplasmic reticulum and myofibrils in isolated rabbit hearts stimulated with isoprenaline. Biochem J 226:113–121PubMedGoogle Scholar
  60. 60.
    Krause T, Gerbershagen MU, Fiege M, Weisshorn R, Wappler F (2004) Dantrolene—a review of its pharmacology, therapeutic use and new developments. Anaesthesia 59:364–373PubMedCrossRefGoogle Scholar
  61. 61.
    Lahat H, Pras E, Olender T, Avidan N, Ben-Asher E, Man O, Levy-Nissenbaum E, Khoury A, Lorber A, Goldman B, Lancet D, Eldar M (2001) A missense mutation in a highly conserved region of CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel. Am J Hum Genet 69:1378–1384PubMedCrossRefGoogle Scholar
  62. 62.
    Lai FA, Erickson HP, Rousseau E, Liu QY, Meissner G (1988) Purification and reconstitution of the calcium release channel from skeletal muscle. Nature 331:315–319PubMedCrossRefGoogle Scholar
  63. 63.
    Lakatta EG (1992) Functional implications of spontaneous sarcoplasmic reticulum Ca2+ release in the heart. Cardiovasc Res 26:193–214PubMedCrossRefGoogle Scholar
  64. 64.
    Leenhardt A, Lucet V, Denjoy I, Grau F, Ngoc DD, Coumel P (1995) Catecholaminergic polymorphic ventricular tachycardia in children. A 7-year follow-up of 21 patients. Circulation 91:1512–1519PubMedGoogle Scholar
  65. 65.
    Lehnart SE, Mongillo M, Bellinger A, Lindegger N, Chen BX, Hsueh W, Reiken S, Wronska A, Drew LJ, Ward CW, Lederer WJ, Kass RS, Morley G, Marks AR (2008) Leaky Ca2+ release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice. J Clin Invest 118:2230–2245PubMedGoogle Scholar
  66. 66.
    Lehnart SE, Wehrens XH, Laitinen PJ, Reiken SR, Deng SX, Cheng Z, Landry DW, Kontula K, Swan H, Marks AR (2004) Sudden death in familial polymorphic ventricular tachycardia associated with calcium release channel (ryanodine receptor) leak. Circulation 109:3208–3214PubMedCrossRefGoogle Scholar
  67. 67.
    Liu N, Colombi B, Memmi M, Zissimopoulos S, Rizzi N, Negri S, Imbriani M, Napolitano C, Lai FA, Priori SG (2006) Arrhythmogenesis in catecholaminergic polymorphic ventricular tachycardia: insights from a RyR2 R4496C knock-in mouse model. Circ Res 99:292–298PubMedCrossRefGoogle Scholar
  68. 68.
    Loke J, MacLennan DH (1998) Malignant hyperthermia and central core disease: disorders of Ca2+ release channels. Am J Med 104:470–486PubMedCrossRefGoogle Scholar
  69. 69.
    Lynch PJ, Tong J, Lehane M, Mallet A, Giblin L, Heffron JJ, Vaughan P, Zafra G, MacLennan DH, McCarthy TV (1999) A mutation in the transmembrane/luminal domain of the ryanodine receptor is associated with abnormal Ca2+ release channel function and severe central core disease. Proc Natl Acad Sci U S A 96:4164–4169PubMedCrossRefGoogle Scholar
  70. 70.
    Ma J (1993) Block by ruthenium red of the ryanodine-activated calcium release channel of skeletal muscle. J Gen Physiol 102:1031–1056PubMedCrossRefGoogle Scholar
  71. 71.
    MacLennan DH, Phillips MS (1992) Malignant hyperthermia. Science 256:789–794PubMedCrossRefGoogle Scholar
  72. 72.
    Marban E, Robinson SW, Wier WG (1986) Mechanisms of arrhythmogenic delayed and early afterdepolarizations in ferret ventricular muscle. J Clin Invest 78:1185–1192PubMedCrossRefGoogle Scholar
  73. 73.
    Marx SO, Gaburjakova J, Gaburjakova M, Henrikson C, Ondrias K, Marks AR (2001) Coupled gating between cardiac calcium release channels (ryanodine receptors). Circ Res 88:1151–1158PubMedCrossRefGoogle Scholar
  74. 74.
    Marx SO, Ondrias K, Marks AR (1998) Coupled gating between individual skeletal muscle Ca2+ release channels (ryanodine receptors). Science 281:818–821PubMedCrossRefGoogle Scholar
  75. 75.
    Marx SO, Reiken S, Hisamatsu Y, Jayaraman T, Burkhoff D, Rosemblit N, Marks AR (2000) PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts. Cell 101:365–376PubMedCrossRefGoogle Scholar
  76. 76.
    McCarthy TV, Quane KA, Lynch PJ (2000) Ryanodine receptor mutations in malignant hyperthermia and central core disease. Hum Mutat 15:410–417PubMedCrossRefGoogle Scholar
  77. 77.
    Meissner G (1994) Ryanodine receptor/Ca2+ release channels and their regulation by endogenous effectors. Annu Rev Physiol 56:485–508PubMedCrossRefGoogle Scholar
  78. 78.
    Meissner G (2004) Molecular regulation of cardiac ryanodine receptor ion channel. Cell Calcium 35:621–628PubMedCrossRefGoogle Scholar
  79. 79.
    Mickelson JR, Gallant EM, Litterer LA, Johnson KM, Rempel WE, Louis CF (1988) Abnormal sarcoplasmic reticulum ryanodine receptor in malignant hyperthermia. J Biol Chem 263:9310–9315PubMedGoogle Scholar
  80. 80.
    Mickelson JR, Louis CF (1996) Malignant hyperthermia: excitation-contraction coupling, Ca2+ release channel, and cell Ca2+ regulation defects. Physiol Rev 76:537–592PubMedGoogle Scholar
  81. 81.
    Monnier N, Krivosic-Horber R, Payen JF, Kozak-Ribbens G, Nivoche Y, Adnet P, Reyford H, Lunardi J (2002) Presence of two different genetic traits in malignant hyperthermia families: implication for genetic analysis, diagnosis, and incidence of malignant hyperthermia susceptibility. Anesthesiology 97:1067–1074PubMedCrossRefGoogle Scholar
  82. 82.
    Moore CP, Rodney G, Zhang JZ, Santacruz-Toloza L, Strasburg G, Hamilton SL (1999) Apocalmodulin and Ca2+ calmodulin bind to the same region on the skeletal muscle Ca2+ release channel. Biochemistry 38:8532–8537PubMedCrossRefGoogle Scholar
  83. 83.
    Nakai J, Dirksen RT, Nguyen HT, Pessah IN, Beam KG, Allen PD (1996) Enhanced dihydropyridine receptor channel activity in the presence of ryanodine receptor. Nature 380:72–75PubMedCrossRefGoogle Scholar
  84. 84.
    Nelson TE (1983) Abnormality in calcium release from skeletal sarcoplasmic reticulum of pigs susceptible to malignant hyperthermia. J Clin Invest 72:862–870PubMedCrossRefGoogle Scholar
  85. 85.
    Oda T, Yano M, Yamamoto T, Tokuhisa T, Okuda S, Doi M, Ohkusa T, Ikeda Y, Kobayashi S, Ikemoto N, Matsuzaki M (2005) Defective regulation of interdomain interactions within the ryanodine receptor plays a key role in the pathogenesis of heart failure. Circulation 111:3400–3410PubMedCrossRefGoogle Scholar
  86. 86.
    Ohnishi ST, Taylor S, Gronert GA (1983) Calcium-induced Ca2+ release from sarcoplasmic reticulum of pigs susceptible to malignant hyperthermia. The effects of halothane and dantrolene. FEBS Lett 161:103–107PubMedCrossRefGoogle Scholar
  87. 87.
    Otsu K, Nishida K, Kimura Y, Kuzuya T, Hori M, Kamada T, Tada M (1994) The point mutation Arg615→Cys in the Ca2+ release channel of skeletal sarcoplasmic reticulum is responsible for hypersensitivity to caffeine and halothane in malignant hyperthermia. J Biol Chem 269:9413–9415PubMedGoogle Scholar
  88. 88.
    Pessah IN, Francini AO, Scales DJ, Waterhouse AL, Casida JE (1986) Calcium-ryanodine receptor complex. Solubilization and partial characterization from skeletal muscle junctional sarcoplasmic reticulum vesicles. J Biol Chem 261:8643–8648PubMedGoogle Scholar
  89. 89.
    Postma AV, Denjoy I, Kamblock J, Alders M, Lupoglazoff JM, Vaksmann G, Dubosq-Bidot L, Sebillon P, Mannens MM, Guicheney P, Wilde AA (2005) Catecholaminergic polymorphic ventricular tachycardia: RYR2 mutations, bradycardia, and follow up of the patients. J Med Genet 42:863–870PubMedCrossRefGoogle Scholar
  90. 90.
    Priori SG, Napolitano C (2005) Cardiac and skeletal muscle disorders caused by mutations in the intracellular Ca2+ release channels. J Clin Invest 115:2033–2038PubMedCrossRefGoogle Scholar
  91. 91.
    Priori SG, Napolitano C (2005) Intracellular calcium handling dysfunction and arrhythmogenesis: a new challenge for the electrophysiologist. Circ Res 97:1077–1079PubMedCrossRefGoogle Scholar
  92. 92.
    Priori SG, Napolitano C, Tiso N, Memmi M, Vignati G, Bloise R, Sorrentino V, Danieli GA (2001) Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation 103:196–200PubMedGoogle Scholar
  93. 93.
    Reiken S, Lacampagne A, Zhou H, Kherani A, Lehnart SE, Ward C, Huang F, Gaburjakova M, Gaburjakova J, Rosemblit N, Warren MS, He KL, Yi GH, Wang J, Burkhoff D, Vassort G, Marks AR (2003) PKA phosphorylation activates the calcium release channel (ryanodine receptor) in skeletal muscle: defective regulation in heart failure. J Cell Biol 160:919–928PubMedCrossRefGoogle Scholar
  94. 94.
    Reiken S, Wehrens XH, Vest JA, Barbone A, Klotz S, Mancini D, Burkhoff D, Marks AR (2003) Beta-blockers restore calcium release channel function and improve cardiac muscle performance in human heart failure. Circulation 107:2459–2466PubMedCrossRefGoogle Scholar
  95. 95.
    Rizzuto R, Pozzan T (2003) When calcium goes wrong: genetic alterations of a ubiquitous signaling route. Nat Genet 34:135–141PubMedCrossRefGoogle Scholar
  96. 96.
    Robinson R, Carpenter D, Shaw MA, Halsall J, Hopkins P (2006) Mutations in RYR1 in malignant hyperthermia and central core disease. Hum Mutat 27:977–989PubMedCrossRefGoogle Scholar
  97. 97.
    Rodney GG, Williams BY, Strasburg GM, Beckingham K, Hamilton SL (2000) Regulation of RYR1 activity by Ca(2+) and calmodulin. Biochemistry 39:7807–7812PubMedCrossRefGoogle Scholar
  98. 98.
    Rosenberg H, Davis M, James D, Pollock N, Stowell K (2007) Malignant hyperthermia. Orphanet J Rare Dis 2:21PubMedCrossRefGoogle Scholar
  99. 99.
    Rosero EB, Adesanya AO, Timaran CH, Joshi GP (2009) Trends and outcomes of malignant hyperthermia in the United States, 2000 to 2005. Anesthesiology 110:89–94PubMedCrossRefGoogle Scholar
  100. 100.
    Rousseau E, Ladine J, Liu QY, Meissner G (1988) Activation of the Ca2+ release channel of skeletal muscle sarcoplasmic reticulum by caffeine and related compounds. Arch Biochem Biophys 267:75–86PubMedCrossRefGoogle Scholar
  101. 101.
    Shannon TR, Ginsburg KS, Bers DM (2002) Quantitative assessment of the SR Ca2+ leak-load relationship. Circ Res 91:594–600PubMedCrossRefGoogle Scholar
  102. 102.
    Smith JS, Rousseau E, Meissner G (1989) Calmodulin modulation of single sarcoplasmic reticulum Ca2 + -release channels from cardiac and skeletal muscle. Circ Res 64:352–359PubMedGoogle Scholar
  103. 103.
    Tanabe T, Beam KG, Adams BA, Niidome T, Numa S (1990) Regions of the skeletal muscle dihydropyridine receptor critical for excitation–contraction coupling. Nature 346:567–569PubMedCrossRefGoogle Scholar
  104. 104.
    Thomas NL, George CH, Lai FA (2004) Functional heterogeneity of ryanodine receptor mutations associated with sudden cardiac death. Cardiovasc Res 64:52–60PubMedCrossRefGoogle Scholar
  105. 105.
    Tiso N, Stephan DA, Nava A, Bagattin A, Devaney JM, Stanchi F, Larderet G, Brahmbhatt B, Brown K, Bauce B, Muriago M, Basso C, Thiene G, Danieli GA, Rampazzo A (2001) Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). Hum Mol Genet 10:189–194PubMedCrossRefGoogle Scholar
  106. 106.
    Tong J, Oyamada H, Demaurex N, Grinstein S, McCarthy TV, MacLennan DH (1997) Caffeine and halothane sensitivity of intracellular Ca2+ release is altered by 15 calcium release channel (ryanodine receptor) mutations associated with malignant hyperthermia and/or central core disease. J Biol Chem 272:26332–26339PubMedCrossRefGoogle Scholar
  107. 107.
    Treves S, Larini F, Menegazzi P, Steinberg TH, Koval M, Vilsen B, Andersen JP, Zorzato F (1994) Alteration of intracellular Ca2+ transients in COS-7 cells transfected with the cDNA encoding skeletal-muscle ryanodine receptor carrying a mutation associated with malignant hyperthermia. Biochem J 301(Pt 3):661–665PubMedGoogle Scholar
  108. 108.
    Ward CW, Reiken S, Marks AR, Marty I, Vassort G, Lacampagne A (2003) Defects in ryanodine receptor calcium release in skeletal muscle from post-myocardial infarct rats. FASEB J 17:1517–1519PubMedGoogle Scholar
  109. 109.
    Watanabe H, Chopra N, Laver D, Hwang HS, Davies SS, Roach DE, Duff HJ, Roden DM, Wilde AA, Knollmann BC (2009) Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in mice and humans. Nat Med 15:380–383PubMedCrossRefGoogle Scholar
  110. 110.
    Wehrens XH, Lehnart SE, Huang F, Vest JA, Reiken SR, Mohler PJ, Sun J, Guatimosim S, Song LS, Rosemblit N, D'Armiento JM, Napolitano C, Memmi M, Priori SG, Lederer WJ, Marks AR (2003) FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death. Cell 113:829–840PubMedCrossRefGoogle Scholar
  111. 111.
    Wehrens XH, Lehnart SE, Reiken SR, Deng SX, Vest JA, Cervantes D, Coromilas J, Landry DW, Marks AR (2004) Protection from cardiac arrhythmia through ryanodine receptor-stabilizing protein calstabin2. Science 304:292–296PubMedCrossRefGoogle Scholar
  112. 112.
    Wehrens XH, Marks AR (2003) Altered function and regulation of cardiac ryanodine receptors in cardiac disease. Trends Biochem Sci 28:671–678PubMedCrossRefGoogle Scholar
  113. 113.
    Witcher DR, Kovacs RJ, Schulman H, Cefali DC, Jones LR (1991) Unique phosphorylation site on the cardiac ryanodine receptor regulates calcium channel activity. J Biol Chem 266:11144–11152PubMedGoogle Scholar
  114. 114.
    Xiao B, Jiang MT, Zhao M, Yang D, Sutherland C, Lai FA, Walsh MP, Warltier DC, Cheng H, Chen SR (2005) Characterization of a novel PKA phosphorylation site, serine-2030, reveals no PKA hyperphosphorylation of the cardiac ryanodine receptor in canine heart failure. Circ Res 96:847–855PubMedCrossRefGoogle Scholar
  115. 115.
    Xu L, Eu JP, Meissner G, Stamler JS (1998) Activation of the cardiac calcium release channel (ryanodine receptor) by poly-S-nitrosylation. Science 279:234–237PubMedCrossRefGoogle Scholar
  116. 116.
    Xu L, Jones R, Meissner G (1993) Effects of local anesthetics on single channel behavior of skeletal muscle calcium release channel. J Gen Physiol 101:207–233PubMedCrossRefGoogle Scholar
  117. 117.
    Yamamoto T, El-Hayek R, Ikemoto N (2000) Postulated role of interdomain interaction within the ryanodine receptor in Ca(2+) channel regulation. J Biol Chem 275:11618–11625PubMedCrossRefGoogle Scholar
  118. 118.
    Yamamoto T, Yano M, Xu X, Uchinoumi H, Tateishi H, Mochizuki M, Oda T, Kobayashi S, Ikemoto N, Matsuzaki M (2008) Identification of target domains of the cardiac ryanodine receptor to correct channel disorder in failing hearts. Circulation 117:762–772PubMedCrossRefGoogle Scholar
  119. 119.
    Yang T, Ta TA, Pessah IN, Allen PD (2003) Functional defects in six ryanodine receptor isoform-1 (RyR1) mutations associated with malignant hyperthermia and their impact on skeletal excitation–contraction coupling. J Biol Chem 278:25722–25730PubMedCrossRefGoogle Scholar
  120. 120.
    Yano M, Kobayashi S, Kohno M, Doi M, Tokuhisa T, Okuda S, Suetsugu M, Hisaoka T, Obayashi M, Ohkusa T, Matsuzaki M (2003) FKBP12.6-mediated stabilization of calcium-release channel (ryanodine receptor) as a novel therapeutic strategy against heart failure. Circulation 107:477–484PubMedCrossRefGoogle Scholar
  121. 121.
    Yano M, Ono K, Ohkusa T, Suetsugu M, Kohno M, Hisaoka T, Kobayashi S, Hisamatsu Y, Yamamoto T, Noguchi N, Takasawa S, Okamoto H, Matsuzaki M (2000) Altered stoichiometry of FKBP12.6 versus ryanodine receptor as a cause of abnormal Ca(2+) leak through ryanodine receptor in heart failure. Circulation 102:2131–2136PubMedGoogle Scholar
  122. 122.
    Zalk R, Lehnart SE, Marks AR (2007) Modulation of the ryanodine receptor and intracellular calcium. Annu Rev Biochem 76:367–385PubMedCrossRefGoogle Scholar
  123. 123.
    Zhou H, Jungbluth H, Sewry CA, Feng L, Bertini E, Bushby K, Straub V, Roper H, Rose MR, Brockington M, Kinali M, Manzur A, Robb S, Appleton R, Messina S, D'Amico A, Quinlivan R, Swash M, Muller CR, Brown S, Treves S, Muntoni F (2007) Molecular mechanisms and phenotypic variation in RYR1-related congenital myopathies. Brain 130:2024–2036PubMedCrossRefGoogle Scholar
  124. 124.
    Zvaritch E, Depreux F, Kraeva N, Loy RE, Goonasekera SA, Boncompagni S, Kraev A, Gramolini AO, Dirksen RT, Franzini-Armstrong C, Seidman CE, Seidman JG, Maclennan DH (2007) An Ryr1I4895T mutation abolishes Ca2+ release channel function and delays development in homozygous offspring of a mutant mouse line. Proc Natl Acad Sci U S A 104:18537–18542PubMedCrossRefGoogle Scholar
  125. 125.
    Zvaritch E, Kraeva N, Bombardier E, McCloy RA, Depreux F, Holmyard D, Kraev A, Seidman CE, Seidman JG, Tupling AR, Maclennan DH (2009) Ca2+ dysregulation in Ryr1I4895T/wt mice causes congenital myopathy with progressive formation of minicores, cores, and nemaline rods. Proc Natl Acad Sci U S A 106:21813–21818PubMedCrossRefGoogle Scholar

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© Springer-Verlag 2010

Authors and Affiliations

  1. 1.Departments of Physiology and Cellular Biophysics and Medicine, Clyde and Helen Wu Center for Molecular CardiologyColumbia University College of Physicians and SurgeonsNew YorkUSA

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