Ryanodine receptor 2 (RYR2) is a protein found primarily in cardiac muscle. In humans, it is encoded by the RYR2gene.[1][2][3] In the process of cardiac calcium-induced calcium release, RYR2 is the major mediator for sarcoplasmic release of stored calcium ions.
The channel is composed of RYR2 homotetramers and FK506-binding proteins found in a 1:4 stoichiometric ratio. Calcium channel function is affected by the specific type of FK506 isomer interacting with the RYR2 protein, due to binding differences and other factors.[4]
Function
The RYR2 protein functions as the major component of a calcium channel located in the sarcoplasmic reticulum that supplies ions to the cardiac muscle during systole. To enable cardiac muscle contraction, calcium influx through voltage-gated L-type calcium channels in the plasma membrane allows calcium ions to bind to RYR2 located on the sarcoplasmic reticulum. This binding causes the release of calcium through RYR2 from the sarcoplasmic reticulum into the cytosol, where it binds to the C domain of troponin, which shifts tropomyosin and allows the myosinATPase to bind to actin, enabling cardiac muscle contraction.[5] RYR2 channels are associated with many cellular functions, including mitochondrial metabolism, gene expression and cell survival, in addition to their role in cardiomyocyte contraction.[6]
Clinical significance
Deleterious mutations of the ryanodine receptor family, and especially the RYR2 receptor, lead to a constellation of pathologies leading to both acute and chronic heart failure collectively known as "Ryanopathies."[7]
↑Otsu K, Willard HF, Khanna VK, Zorzato F, Green NM, MacLennan DH (September 1990). "Molecular cloning of cDNA encoding the Ca2+ release channel (ryanodine receptor) of rabbit cardiac muscle sarcoplasmic reticulum". J Biol Chem. 265 (23): 13472–83. PMID2380170.
↑Otsu K, Fujii J, Periasamy M, Difilippantonio M, Uppender M, Ward DC, MacLennan DH (October 1993). "Chromosome mapping of five human cardiac and skeletal muscle sarcoplasmic reticulum protein genes". Genomics. 17 (2): 507–9. doi:10.1006/geno.1993.1357. PMID8406504.
↑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 (February 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 (3): 189–94. doi:10.1093/hmg/10.3.189. PMID11159936.
↑ 10.010.110.210.3Marx SO, Reiken S, Hisamatsu Y, Jayaraman T, Burkhoff D, Rosemblit N, Marks AR (May 2000). "PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts". Cell. 101 (4): 365–76. doi:10.1016/S0092-8674(00)80847-8. PMID10830164.
↑Meyers MB, Pickel VM, Sheu SS, Sharma VK, Scotto KW, Fishman GI (November 1995). "Association of sorcin with the cardiac ryanodine receptor". J. Biol. Chem. 270 (44): 26411–8. doi:10.1074/jbc.270.44.26411. PMID7592856.
Further reading
Ogawa Y, Kurebayashi N, Murayama T (1999). "Ryanodine receptor isoforms in excitation-contraction coupling". Adv. Biophys. 36: 27–64. doi:10.1016/S0065-227X(99)80004-5. PMID10463072.
Marks AR, Priori S, Memmi M, Kontula K, Laitinen PJ (2002). "Involvement of the cardiac ryanodine receptor/calcium release channel in catecholaminergic polymorphic ventricular tachycardia". J. Cell. Physiol. 190 (1): 1–6. doi:10.1002/jcp.10031. PMID11807805.
Marks AR (2002). "Ryanodine receptors, FKBP12, and heart failure". Front. Biosci. 7: d970–7. doi:10.2741/marks. PMID11897558.
Ma J, Hayek SM, Bhat MB (2005). "Membrane topology and membrane retention of the ryanodine receptor calcium release channel". Cell Biochem. Biophys. 40 (2): 207–24. doi:10.1385/CBB:40:2:207. PMID15054223.
Meyers MB, Pickel VM, Sheu SS, Sharma VK, Scotto KW, Fishman GI (1995). "Association of sorcin with the cardiac ryanodine receptor". J. Biol. Chem. 270 (44): 26411–8. doi:10.1074/jbc.270.44.26411. PMID7592856.
Rampazzo A, Nava A, Erne P, Eberhard M, Vian E, Slomp P, Tiso N, Thiene G, Danieli GA (1996). "A new locus for arrhythmogenic right ventricular cardiomyopathy (ARVD2) maps to chromosome 1q42-q43". Hum. Mol. Genet. 4 (11): 2151–4. doi:10.1093/hmg/4.11.2151. PMID8589694.
Martin C, Chapman KE, Seckl JR, Ashley RH (1998). "Partial cloning and differential expression of ryanodine receptor/calcium-release channel genes in human tissues including the hippocampus and cerebellum". Neuroscience. 85 (1): 205–16. doi:10.1016/S0306-4522(97)00612-X. PMID9607712.
Mori F, Fukaya M, Abe H, Wakabayashi K, Watanabe M (2000). "Developmental changes in expression of the three ryanodine receptor mRNAs in the mouse brain". Neurosci. Lett. 285 (1): 57–60. doi:10.1016/S0304-3940(00)01046-6. PMID10788707.
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 (4): 365–76. doi:10.1016/S0092-8674(00)80847-8. PMID10830164.
Laitinen PJ, Brown KM, Piippo K, Swan H, Devaney JM, Brahmbhatt B, Donarum EA, Marino M, Tiso N, Viitasalo M, Toivonen L, Stephan DA, Kontula K (2001). "Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia". Circulation. 103 (4): 485–90. doi:10.1161/01.cir.103.4.485. PMID11157710.
Priori SG, Napolitano C, Tiso N, Memmi M, Vignati G, Bloise R, Sorrentino V, Danieli GA (2004). "Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia". Circulation. 103 (2): 196–200. doi:10.1161/01.cir.103.2.196. PMID11208676.
Jeyakumar LH, Ballester L, Cheng DS, McIntyre JO, Chang P, Olivey HE, Rollins-Smith L, Barnett JV, Murray K, Xin HB, Fleischer S (2001). "FKBP binding characteristics of cardiac microsomes from diverse vertebrates". Biochem. Biophys. Res. Commun. 281 (4): 979–86. doi:10.1006/bbrc.2001.4444. PMID11237759.