Abstract
Intracellular calcium release channels (ryanodine receptors, RyR) are present on the sarcoplasmic reticulum (SR) in cardiomyocytes and are required for excitation-contraction (EC) coupling in cardiac muscle. Each RyR channel consists of four pore-forming subunits that contain large cytoplasmic domains, which serve as scaffolds for proteins that regulate the activity of the channel. An important regulatory protein is calstabin2 (FKBP12.6), a subunit that stabilizes the closed state of the channel to prevent aberrant calcium (Ca2+) leak from the SR.1 Direct targeting of several protein kinases and phosphatases to the type 2 cardiac RyR channel (RyR2) allows for rapid and localized modulation of SR Ca2+ release in response to extracellular signals.2
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References
Jayaraman T, Brillantes AM, Timerman AP, et al. FK506 binding protein associated with the calcium release channel (ryanodine receptor). J Biol Chem 1992;267:9474–9477.
Marx SO, Reiken S, Hisamatsu Y, et al. Phosphor-ylation-dependent regulation of ryanodine receptors. A novel role for leucine/isoleucine zippers. J Cell Biol 2001;153(4):699–708.
Tiso N, Stephan DA, Nava A, et al. Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). Hum Mol Genet 2001;10(3):189–194.
Priori SG, Napolitano C, Tiso N, et al. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation 2001;103(2):196–200.
Laitinen PJ, Brown KM, Piippo K, et al. Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia. Circulation 2001;103(4):485–490.
Marx SO, Reiken S, Hisamatsu Y, et al. PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): Defective regulation in failing hearts. Cell 2000;101:365–376.
Yano M, Ono K, Ohkusa T, et al. Altered stoichiometry of FKBP12.6 versus ryanodine receptor as a cause of abnormal Ca2+ leak through ryanodine receptor in heart failure. Circulation 2000;102(17): 2131–2136.
Yano M, Kobayashi S, Kohno M, et al. FKBP12.6-mediated stabilization of calcium-release channel (ryanodine receptor) as a novel therapeutic strategy against heart failure. Circulation 2003;107(3): 477–484.
Kohno M, Yano M, Kobayashi S, et al. A new cardioprotective agent, JTV519, improves defective channel gating of ryanodine receptor in heart failure. AmJPhysiol Heart Circ Physiol 2003;284(3): H1035–1042.
Wehrens XH, Lehnart SE, Reiken SR, et al. Protection from cardiac arrhythmia through ryanodine receptor-stabilizing protein calstabin 2. Science 2004;304(5668):292–296.
Wehrens XH, Lehnart SE, Reiken S, etal. Enhancing calstabin binding to ryanodine receptors improves cardiac and skeletal muscle function in heart failure. Proc Natl Acad Sci USA 2005;102(27):9607–9612.
Nabauer M, Callewart G, Cleeman L, Morad M. Regulation of calcium release is gated by calcium current, not gating charge, in cardiac, myocytes. Science 1989;244:800–803.
Bers DM, Guo T. Calcium signaling in cardiac ventricular myocytes. Ann NY Acad Sci 2005;1047: 86–98.
Fabiato A. Time and calcium dependence of activation and inactivation of calcium-induced release of calcium from the sarcoplasmic reticulum of a skinned canine cardiac Purkinje cell. J Gen Physiol 1985;85:247–289.
Wehrens XHT, Lehnart SE, Marks AR. Intracellular calcium release channels and cardiac disease. Annu Rev Physiol 2005;67:69–98.
Cheng H, Lederer WJ, Cannell MB. Calcium sparks: Elementary events underlying excitationcontraction coupling in heart muscle. Science 1993; 262(5134):740–744.
Lindegger N, Niggli E. Paradoxical SR Ca2+ release in guinea-pig cardiac myocytes after β-adrenergic stimulation revealed by two-photon photolysis of caged Ca2+. J Physiol 2005;565(3):801–813.
Cannell MB, Cheng H, Lederer WJ. The control of calcium release in heart muscle. Science 1995; 268(5213):1045–1049.
Marx SO, Gaburjakova J, Gaburjakova M, Henrikson C, Ondrias K, Marks AR. Coupled gating between cardiac calcium release channels (ryanodine receptors). Circ Res 2001;88(11):1151–1158.
Brochet DX, Yang D, Di Maio A, Lederer WJ, Franzini-Armstrong C, Cheng H. Ca2+ blinks: Rapid nanoscopic store calcium signaling. Proc Natl Acad Sci USA 2005;102(8):3099–3104.
Otsu K, Willard HF, Khanna VK, Zorzato F, Green NM, MacLennan DH. Molecular cloning of cDNA encoding the Ca2+ release channel (ryanodine receptor) of rabbit cardiac muscle sarcoplasmic reticulum. J Biol Chem 1990;265:13472–13483.
Tunwell RE, Wickenden C, Bertrand BM, et al. The human cardiac muscle ryanodine receptor-calcium release channel: Identification, primary structure and topological analysis. Biochem J 1996;318:477–487.
Marks AR, Tempst P, Hwang KS, et al. Molecular cloning and characterization of the ryanodine receptor/junctional channel complex cDNA from skeletal muscle sarcoplasmic reticulum. Proc Natl Acad Sci USA 1989;86:8683–8687.
Lam E, Martin MM, Timerman AP, et al. A novel FK506 binding protein can mediate the immuno-suppressive effects of FK506 and is associated with the cardiac ryanodine receptor. J Biol Chem 1995; 270:26511–26522.
Brillantes AB, Ondrias K, Scott A, et al. Stabilization of calcium release channel (ryanodine receptor) function by FK506-binding protein. Cell 1994; 77(4):513–523.
Wehrens XH, Lehnart SE, Huang F, et al. FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death. Cell 2003;113(7): 829–840.
Lehnart SE, Huang F, Marx SO, Marks AR. Immunophilins and coupled gating of ryanodine receptors. Curr Top Med Chem 2003;3(12):1383–1391.
Chu A, Sumbilla C, Inesi G, Jay SD, Campbell KP. Specific association of calmodulin-dependent protein kinase and related substrates with the junctional sarcoplasmic reticulum of skeletal muscle. Biochemistry 1990;29(25):5899–5905.
Meyers MB, Pickel VM, Sheu SS, Sharma VK, Scotto KW, Fishman GI. Association of sorcin with the cardiac ryanodine receptor. J Biol Chem 1995; 270(44):26411–26418.
Currie S, Loughrey CM, Craig MA, Smith GL. Calcium/calmodulin-dependent protein kinase IIdelta associates with the ryanodine receptor complex and regulates channel function in rabbit heart. Biochem J 2004;377(Pt. 2):357–366.
Wehrens XH, Lehnart SE, Reiken SR, Marks AR. Ca2+/calmodulin-dependent protein kinase II phosphorylation regulates the cardiac ryanodine receptor. Circ Res 2004;94(6):e61–70.
Zhang L, Kelley J, Schmeisser G, Kobayashi YM, Jones LR. Complex formation between junctin, triadin, calsequestrin, and the ryanodine receptor. Proteins of the cardiac junctional sarcoplasmic reticulum membrane. J Biol Chem 1997;272(37): 23389–23397.
Gyorke I, Hester N, Jones LR, Gyorke S. The role of calsequestrin, triadin, and junctin in conferring cardiac ryanodine receptor responsiveness to luminal calcium. Biophys J 2004;86:2121–2128.
Terentyev D, Viatchenko-Karpinski S, Gyorke I, Volpe P, Williams SC, Gyorke S. Calsequestrin determines the functional size and stability of cardiac intracellular calcium stores: Mechanism for hereditary arrhythmia. Proc Natl Acad Sci USA 2003;100(20):11759–11764.
Jiang D, Wang R, Xiao B, et al. 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 2005; 97(11):1173–1181.
Stull LB, Leppo MK, Marban E, Janssen PM. Physiological determinants of contractile force generation and calcium handling in mouse myocardium. J Mol Cell Cardiol 2002;34(10):1367–1376.
Braz JC, Gregory K, Pathak A, et al. PKC-alpha regulates cardiac contractility and propensity toward heart failure. Nat Med 2004;10(3):248–254.
Lefkowitz RJ, Rockman HA, Koch WJ. Catecho-lamines, cardiac beta-adrenergic receptors, and heart failure. Circulation 2000;101(14):1634–1637.
Jones LR, Simmerman HK, Wilson WW, Gurd FR, Wegener AD. Purification and characterization of phospholamban from canine cardiac sarcoplasmic reticulum. J Biol Chem 1985;260(12):7721–7730.
Gomez AM, Valdivia HH, Cheng H, et al. Defective excitation-contraction coupling in experimental cardiac hypertrophy and heart failure. Science 1997; 276(5313):800–806.
Hain J, Onoue H, Mayrleitner M, Fleischer S, Schindler H. Phosphorylation modulates the function of the calcium release channel of sarcoplasmic reticulum from cardiac muscle. J Biol Chem 1995;270(5): 2074–2081.
Valdivia HH, Kaplan JH, Ellis-Davies GC, Lederer WJ. Rapid adaptation of cardiac ryanodine receptors: Modulation by Mg2+ and phosphorylation. Science 1995;267(5206):1997–2000.
Wehrens XH, Marks AR. Ryanodine Receptors. Structure, Function and Dysfunction in Clinical Disease. New York: Springer, 2004.
Xiao B, Jiang MT, Zhao M, et al. Characterization of a novel PKA phosphorylation site, serine-2030, reveals no PKA hyperphosphorylation of the cardiac ryanodine receptor in canine heart failure. Circ Res 2005;96(8):847–855.
Wehrens XH, Lehnart SE, Reiken S, Vest JA, Wronska A, Marks AR. Ryanodine receptor/ calcium release channel PKA phosphorylation: A critical mediator of heart failure progression. Proc Natl Acad Sci USA 2006;103(3):511–518.
Lokuta AJ, Rogers TB, Lederer WJ, Valdivia HH. Modulation of cardiac ryanodine receptors of swine and rabbit by a phosphorylation-dephosphorylation mechanism. J Phys 1995;487(Pt. 3):609–622.
Lehnart SE, Wehrens XH, Reiken S, et al. Phosphodiesterase 4D deficiency in the ryanodine-receptor complex promotes heart failure and arrhythmias. Cell 2005;123(1):25–35.
d’Amati G, Bagattin A, Bauce B, et al. Juvenile sudden death in a family with polymorphic ventricular arrhythmias caused by a novel RyR2 gene mutation: Evidence of specific morphological substrates. Hum Pathol 2005;36(7):761–767.
Tiziana di Gioia CR, Autore C, Romeo DM, et al. Sudden cardiac death in younger adults: Autopsy diagnosis as a tool for preventive medicine. Hum Pathol 2006;37(7):794–801.
Creighton W, Virmani R, Kutys R, Burke A. Identification of novel missense mutations of cardiac ryanodine receptor gene in exercise-induced sudden death at autopsy. J Mol Diagn 2006;8(1):62–67.
Tester DJ, Kopplin LJ, Will ML, Ackerman MJ. Spectrum and prevalence of cardiac ryanodine receptor (RyR2) mutations in a cohort of unrelated patients referred explicitly for long QT syndrome genetic testing. Heart Rhythm 2005;2(10):1099–1105.
Bauce B, Rampazzo A, Basso C, et al. Screening for ryanodine receptor type 2 mutations in families with effort-induced polymorphic ventricular arrhythmias and sudden death: Early diagnosis of asymptomatic carriers. J Am Coll Cardiol 2002; 40(2):341–349.
Tester DJ, Spoon DB, Valdivia HH, Makielski JC, Ackerman MJ. Targeted mutational analysis of the cardiac ryanodine receptor (RyR2) in sudden unexplained death: A molecular autopsy of 51 medical examiner/coroner’s cases. Mayo Clin Proc 2004; 79(11):1380–1384.
Postma AV, Denjoy I, Kamblock J, et al. Catecho-laminergic polymorphic ventricular tachycardia: RYR2 mutations, bradycardia, and follow up of the patients. J Med Genet 2005;42(11):863–870.
Priori SG, Napolitano C, Memmi M, et al. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. Circulation 2002;106(1):69–74.
Laitinen PJ, Swan H, Kontula K. Molecular genetics of exercise-induced polymorphic ventricular tachycardia: Identification of three novel cardiac ryanodine receptor mutations and two common calsequestrin 2 amino-acid polymorphisms. Eur J Hum Genet 2003;11(11):888–891.
Bagattin A, Veronese C, Bauce B, et al. Denaturing HPLC-based approach for detecting RYR2 mutations involved in malignant arrhythmias. Clin Chem 2004;50(7):1148–1155.
Aizawa Y, Ueda K, Komura S, et al. A novel mutation in FKBP12.6 binding region of the human cardiac ryanodine receptor gene (R2401H) in a Japanese patient with catecholaminergic polymorphic ventricular tachycardia. Int J Cardiol 2005; 99(2):343–345.
Hasdemir C, Priori SG, Overholt E, Lazzara R. Catecholaminergic polymorphic ventricular tachycardia, recurrent syncope, and implantable loop recorder. J Cardiovasc Electrophysiol 2004;15(6): 729.
Allouis M, Probst V, Jaafar P, Schott JJ, Le Marec H. Unusual clinical presentation in a family with catecholaminergic polymorphic ventricular tachycardia due to a G14876A ryanodine receptor gene mutation. Am J Cardiol 2005;95(5):700–702.
Sumitomo N, Harada K, Nagashima M, et al. Catecholaminergic polymorphic ventricular tachycardia: Electrocardiographic characteristics and optimal therapeutic strategies to prevent sudden death. Heart 2003;89(1):66–70.
Cerrone M, Colombi B, Santoro M, et al. Bidirectional ventricular tachycardia and fibrillation elicited in a knock-in mouse model carrier of a mutation in the cardiac ryanodine receptor. Circ Res2005;96(10):e77–82.
Kannankeril P, Mitchell B, Goonasekera S, et al. Mice with the R176Q cardiac ryanodine receptor mutation exhibit catecholamine-induced ventricular tachycardia and mild cardiomyopathy. Proc Natl Acad Sci USA 2006;103(32):12179–12184.
Lehnart SE, Wehrens XHT, Laitinen PJ, et al. Sudden death in familial polymorphic ventricular tachycardia associated with calcium release channel (ryanodine receptor) leak. Circulation 2004(109): r113–119.
George CH, Jundi H, Walters N, Thomas NL, West RR, Lai FA. Arrhythmogenic mutation-linked defects in ryanodine receptor autoregulation reveal a novel mechanism of Ca2+ release channel dysfunction. Circ Res 2006;98(1):88–97.
George CH, Higgs GV, Lai FA. Ryanodine receptor mutations associated with stress-induced ventricular tachycardia mediate increased calcium release in stimulated cardiomyocytes. Circ Res 2003;93(6): 531–540.
Swan H, Piippo K, Viitasalo M, et al. Arrhythmic disorder mapped to chromosome 1q42-q43 causes malignant polymorphic ventricular tachycardia in structurally normal hearts. J Am Coll Cardiol 1999; 34(7):2035–2042.
Lehnart SE, Terrenoire C, Reiken S, et al. Stabilization of cardiac ryanodine receptor prevents intracellular calcium leak and arrhythmias. Proc Natl Acad Sci USA 2006;103(20):7906–7910.
Jiang D, Xiao B, Yang D, et al. RyR2 mutations linked to ventricular tachycardia and sudden death reduce the threshold for store-overload-induced Ca2+ release (SOICR). Proc Natl Acad Sci USA 2004;101(35):13062–13067.
Terentyev D, Nori A, Santoro M, et al. Abnormal interactions of calsequestrin with the ryanodine receptor calcium release channel complex linked to exercise-induced sudden cardiac death. Circ Res 2006;98(9):1151–1158.
Corrado D, Thiene G. Arrhythmogenic right ventricular cardiomyopathy/dysplasia: Clinical impact of molecular genetic studies. Circulation 2006; 113(13):1634–1637.
Priori SG, Napolitano C. Intracellular calcium handling dysfunction and arrhythmogenesis: A new challenge for the electrophysiologist. Circ Res 2005;97(11):1077–1079.
Ma G, Brady WJ, Pollack M, Chan TC. Electrocardiographic manifestations: Digitalis toxicity. J EmergMed 2001;20(2):145–152.
Scoote M, Williams AJ. The cardiac ryanodine receptor (calcium release channel): Emerging role in heart failure and arrhythmia pathogenesis. Cardiovasc Res 2002;56(3):359–372.
Wehrens XH, Lehnart SE, Marks AR. Ryanodine receptor-targeted anti-arrhythmic therapy. Ann NY Acad Sci 2005;1047:366–375.
Santana LF, Cheng H, Gomez AM, Cannell MB, Lederer WJ. Relation between the sarcolemmal Ca2+ current and Ca2+ sparks and local control theories for cardiac excitation-contraction coupling. Circ Res 1996;78(1):166–171.
Bers DM, Eisner DA, Valdivia HH. Sarcoplasmic reticulum Ca2+ and heart failure: Roles of diastolic leak and Ca2+ transport. Circ Res 2003;93(6):487–490.
Daaka Y, Luttrell LM, Lefkowitz RJ. Switching of the coupling of the beta2-adrenergic receptor to different G proteins by protein kinase A. Nature 1997;390(6655):88–91.
Marks AR. Ryanodine receptors/calcium release channels in heart failure and sudden cardiac death. JMol Cell Cardiol 2001;33(4):615–624.
Reiken S, Wehrens XH, Vest JA, et al. Beta-blockers restore calcium release channel function and improve cardiac muscle performance in human heart failure. Circulation 2003;107(19):2459–2466.
De Rosa G, Delogu AB, Piastra M, Chiaretti A, Bloise R, Priori SG. Catecholaminergic polymorphic ventricular tachycardia: Successful emergency treatment with intravenous propranolol. Pediatr Emerg Care 2004;20(3):175–177.
Fisher JD, Krikler D, Hallidie-Smith KA. Familial polymorphic ventricular arrhythmias: A quarter century of successful medical treatment based on serial exercise-pharmacologic testing. J Am Coll Cardiol 1999;34(7):2015–2022.
Huang F, Shan J, Reiken S, Wehrens XH, Marks AR. Analysis of calstabin2 (FKBP12.6)-ryanodine receptor interactions: Rescue of heart failure by calstabin2 in mice. Proc Natl Acad Sci USA 2006; 103(9):3456–3461.
Wehrens XH, Marks AR. Novel therapeutic approaches for heart failure by normalising calcium cycling. Nat Rev Drug Discov 2004;3:565–573.
Venetucci LA, Trafford AW, Diaz ME, O’Neill SC, Eisner DA. Reducing ryanodine receptor open probability as a means to abolish spontaneous Ca2+ release and increase Ca2+ transient amplitude in adult ventricular myocytes. Circ Res 2006; 98(10):1299–1305.
Pratt NG. Pathophysiology of heart failure: Neuroendocrine response. Crit Care Nurs Q 1995;18(1): 22–31.
Yano M, Yamamoto T, Ikeda Y, Matsuzaki M. Mechanisms of disease: Ryanodine receptor defects in heart failure and fatal arrhythmia. Nat Clin Pract Cardiovasc Med 2006;3(1):43–52.
Farr MA, Basson CT. Sparking the failing heart. N Engl J Med 2004;351(2):185–187.
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Sood, S., Wehrens, X.H. (2008). Calcium Release Channels (Ryanodine Receptors) and Arrhythmogenesis. In: Gussak, I., Antzelevitch, C., Wilde, A.A.M., Friedman, P.A., Ackerman, M.J., Shen, WK. (eds) Electrical Diseases of the Heart. Springer, London. https://doi.org/10.1007/978-1-84628-854-8_14
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