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Gene Review

RYR2  -  ryanodine receptor 2 (cardiac)

Homo sapiens

Synonyms: ARVC2, ARVD2, Cardiac muscle ryanodine receptor, Cardiac muscle ryanodine receptor-calcium release channel, RYR-2, ...
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Disease relevance of RYR2


Psychiatry related information on RYR2


High impact information on RYR2


Chemical compound and disease context of RYR2


Biological context of RYR2

  • Fifty-three single exons, possibly targeted by mutations, were identified by comparison with the distribution of pathogenic mutations of the RYR1 gene, the skeletal muscle counterpart of RYR2 [1].
  • However, we identified two single nucleotide polymorphisms (SNPs) in exon 37 of the human RYR2 gene which lead to the amino acid exchanges G1885E and G1886S, respectively [2].
  • Mutations of two myocardial calcium signaling molecules, ryanodine receptor 2 (RYR2) and calsequestrin 2 (CASQ2), may cause catecholaminergic polymorphic ventricular tachycardia (CPVT), a severe inherited arrhythmic disease manifesting with salvoes of exercise-induced bidirectional and polymorphic tachycardias [14].
  • These data demonstrate that defective regulation of RyR causes altered cellular phenotype via profound perturbations in intracellular Ca2+ signaling and highlight a key modulatory role of FKBP12.6 in hRyR2 Ca2+ channel function [15].
  • Cells stably expressing recombinant human RyR2 (Chinese hamster ovary cells, CHOhRyR2) had similar resting cytoplasmic Ca2+ levels ([Ca2+]c) to wild-type CHO cells (CHOWT) but exhibited increased cytoplasmic Ca2+ flux associated with decreased cell viability and proliferation [15].

Anatomical context of RYR2


Associations of RYR2 with chemical compounds

  • In contrast to the RYR1 isoform, the cardiac RYR2 isoform was unaffected by dantrolene, both in native cardiac SR vesicles and when heterologously expressed in HEK-293 cells [18].
  • These analyses revealed that RyR2(T1874-GFP) functions as a caffeine- and ryanodine-sensitive Ca(2+) release channel and displays Ca(2+) dependence and [(3)H]ryanodine binding properties similar to those of the wild type RyR2 [19].
  • Substitution of Val(2322) for leucine (as in IP(3)R1) or isoleucine (as in RyR2) decreased the binding efficiency and shifted the selectivity to FKBP12.6; substitution of Val(2322) for aspartate completely abolished the FKBP interaction [20].
  • The magnitude of Ca(2+) release in CHO(hRyR2) cells in response to stimulation by 4-chloro- m -cresol was in direct proportion to the expression levels of hRyR2 [21].
  • Isoproterenol and forskolin elevated cyclic-AMP to similar magnitudes in all cells and were associated with equivalent hyperphosphorylation of mutant and WT hRyR2 [22].

Physical interactions of RYR2

  • 6. However, expression of a large RyR2 C-terminal construct in mammalian cells encompassing the pore-forming transmembrane domains exhibits rapamycin-sensitive binding specifically to FKBP12.6 but not to FKBP12 [23].

Regulatory relationships of RYR2

  • There was negligible hRyR2-induced subcellular redistribution of FKBP12 [21].
  • These observations support the idea that the expression of the RyR2 isoform is up-regulated both in pregnancy and in TGF-beta-treated cultured myometrial cells [17].
  • At low Ca(2+) concentrations (<1 microM), CaM activates RyR1 and RyR3 and inhibits RyR2 [24].
  • Cardiac RyR2 activity was inhibited by GSTO1-1, whereas skeletal muscle RyR1 activity was potentiated [25].
  • PKA phosphorylation of RyR2 induces dissociation of the regulatory protein FKBP12.6 resulting in channels with increased sensitivity to Ca2+-induced Ca2+ release [26].

Other interactions of RYR2

  • Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2) [3].
  • Co-expression of a ryanodine binding deficient mutant of RyR2, RyR2 (I4827T), with RyR3 (wt) restored [(3)H]ryanodine binding to the mutant [27].
  • These data, combined with our previous findings, show that RYR2 mutations are present in at least 6/16 (38%) of the catecholaminergic polymorphic ventricular tachycardia families, while CASQ2 mutations must be a rare cause of CPVT [14].
  • After treatment with TGF-beta, both RyR2 and RyR3 mRNAs could be detected in cultured myometrial cells [17].
  • CLIC-2 (0.2-10 microM) added to the cytoplasmic side of RyR2 channels in lipid bilayers depressed activity in a reversible, voltage-independent, manner in the presence of activating (10-100 microM) or sub-activating (100 nM) cytoplasmic Ca2+ concentrations [28].

Analytical, diagnostic and therapeutic context of RYR2

  • METHODS: ARVC patients were screened for mutations in the RYR2 gene by denaturing HPLC and DNA sequencing [2].
  • Consistent with sedimentation and immunoblotting studies on the hRyR-2 protein, sequence analysis of ten overlapping cDNA clones reveals an open reading frame of 14901 nucleotides encoding a protein of 4967 amino acid residues with a predicted molecular mass of 564 569 Da for hRyR-2 [29].
  • Sequence alignment of hRyR-2 with other RyR isoforms indicates a high level of overall identity within the RyR family, with the exception of two important regions that exhibit substantial variability [29].
  • Six hydrophobic stretches, which are present within the hRyR-2 C-terminal 500 amino acids and are conserved in all RyR sequences, may be involved in forming the transmembrane domain that constitutes the Ca(2+)-conducting pathway, in agreement with competitive ELISA studies with a RyR-2-specific antibody [29].
  • The impact of coexpressing dsRed-tagged cytoplasmic domains of RyR2 on intracellular Ca(2+) phenotype was assessed using confocal microscopy coupled with parallel determination of in situ protein: protein interaction using fluorescence resonance energy transfer (FRET) [30].


  1. Denaturing HPLC-based approach for detecting RYR2 mutations involved in malignant arrhythmias. Bagattin, A., Veronese, C., Bauce, B., Wuyts, W., Settimo, L., Nava, A., Rampazzo, A., Danieli, G.A. Clin. Chem. (2004) [Pubmed]
  2. Composite polymorphisms in the ryanodine receptor 2 gene associated with arrhythmogenic right ventricular cardiomyopathy. Milting, H., Lukas, N., Klauke, B., Körfer, R., Perrot, A., Osterziel, K.J., Vogt, J., Peters, S., Thieleczek, R., Varsányi, M. Cardiovasc. Res. (2006) [Pubmed]
  3. Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). Tiso, N., Stephan, D.A., Nava, A., Bagattin, A., Devaney, J.M., Stanchi, F., Larderet, G., Brahmbhatt, B., Brown, K., Bauce, B., Muriago, M., Basso, C., Thiene, G., Danieli, G.A., Rampazzo, A. Hum. Mol. Genet. (2001) [Pubmed]
  4. Ryanodine receptor channelopathies. Benkusky, N.A., Farrell, E.F., Valdivia, H.H. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  5. Screening for ryanodine receptor type 2 mutations in families with effort-induced polymorphic ventricular arrhythmias and sudden death: early diagnosis of asymptomatic carriers. Bauce, B., Rampazzo, A., Basso, C., Bagattin, A., Daliento, L., Tiso, N., Turrini, P., Thiene, G., Danieli, G.A., Nava, A. J. Am. Coll. Cardiol. (2002) [Pubmed]
  6. Phosphodiesterase 4D deficiency in the ryanodine-receptor complex promotes heart failure and arrhythmias. Lehnart, S.E., Wehrens, X.H., Reiken, S., Warrier, S., Belevych, A.E., Harvey, R.D., Richter, W., Jin, S.L., Conti, M., Marks, A.R. Cell (2005) [Pubmed]
  7. PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts. Marx, S.O., Reiken, S., Hisamatsu, Y., Jayaraman, T., Burkhoff, D., Rosemblit, N., Marks, A.R. Cell (2000) [Pubmed]
  8. Cardiac and skeletal muscle disorders caused by mutations in the intracellular Ca2+ release channels. Priori, S.G., Napolitano, C. J. Clin. Invest. (2005) [Pubmed]
  9. Altered function and regulation of cardiac ryanodine receptors in cardiac disease. Wehrens, X.H., Marks, A.R. Trends Biochem. Sci. (2003) [Pubmed]
  10. Isoform-specific interactions between halothane and the ryanodine receptor Ca(2+)-release channel: implications for malignant hyperthermia and the protein theory of anaesthetic action. Frömming, G.R., Ohlendieck, K. Naturwissenschaften (1999) [Pubmed]
  11. 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. Jiang, D., Wang, R., Xiao, B., Kong, H., Hunt, D.J., Choi, P., Zhang, L., Chen, S.R. Circ. Res. (2005) [Pubmed]
  12. Adenosine A(2A) receptors are expressed in human atrial myocytes and modulate spontaneous sarcoplasmic reticulum calcium release. Hove-Madsen, L., Prat-Vidal, C., Llach, A., Ciruela, F., Casad??, V., Lluis, C., Bayes-Genis, A., Cinca, J., Franco, R. Cardiovasc. Res. (2006) [Pubmed]
  13. Calcium channel antagonism reduces exercise-induced ventricular arrhythmias in catecholaminergic polymorphic ventricular tachycardia patients with RyR2 mutations. Swan, H., Laitinen, P., Kontula, K., Toivonen, L. J. Cardiovasc. Electrophysiol. (2005) [Pubmed]
  14. Molecular genetics of exercise-induced polymorphic ventricular tachycardia: identification of three novel cardiac ryanodine receptor mutations and two common calsequestrin 2 amino-acid polymorphisms. Laitinen, P.J., Swan, H., Kontula, K. Eur. J. Hum. Genet. (2003) [Pubmed]
  15. Dysregulated ryanodine receptors mediate cellular toxicity: restoration of normal phenotype by FKBP12.6. George, C.H., Higgs, G.V., Mackrill, J.J., Lai, F.A. J. Biol. Chem. (2003) [Pubmed]
  16. Expression of the ryanodine receptor isoforms in immune cells. Hosoi, E., Nishizaki, C., Gallagher, K.L., Wyre, H.W., Matsuo, Y., Sei, Y. J. Immunol. (2001) [Pubmed]
  17. Differential expression of ryanodine receptor RyR2 mRNA in the non-pregnant and pregnant human myometrium. Awad, S.S., Lamb, H.K., Morgan, J.M., Dunlop, W., Gillespie, J.I. Biochem. J. (1997) [Pubmed]
  18. Dantrolene inhibition of ryanodine receptor Ca2+ release channels. Molecular mechanism and isoform selectivity. Zhao, F., Li, P., Chen, S.R., Louis, C.F., Fruen, B.R. J. Biol. Chem. (2001) [Pubmed]
  19. Three-dimensional localization of divergent region 3 of the ryanodine receptor to the clamp-shaped structures adjacent to the FKBP binding sites. Zhang, J., Liu, Z., Masumiya, H., Wang, R., Jiang, D., Li, F., Wagenknecht, T., Chen, S.R. J. Biol. Chem. (2003) [Pubmed]
  20. The conserved sites for the FK506-binding proteins in ryanodine receptors and inositol 1,4,5-trisphosphate receptors are structurally and functionally different. Bultynck, G., Rossi, D., Callewaert, G., Missiaen, L., Sorrentino, V., Parys, J.B., De Smedt, H. J. Biol. Chem. (2001) [Pubmed]
  21. In situ modulation of the human cardiac ryanodine receptor (hRyR2) by FKBP12.6. George, C.H., Sorathia, R., Bertrand, B.M., Lai, F.A. Biochem. J. (2003) [Pubmed]
  22. Ryanodine receptor mutations associated with stress-induced ventricular tachycardia mediate increased calcium release in stimulated cardiomyocytes. George, C.H., Higgs, G.V., Lai, F.A. Circ. Res. (2003) [Pubmed]
  23. Interaction of FKBP12.6 with the cardiac ryanodine receptor C-terminal domain. Zissimopoulos, S., Lai, F.A. J. Biol. Chem. (2005) [Pubmed]
  24. Calmodulin regulation and identification of calmodulin binding region of type-3 ryanodine receptor calcium release channel. Yamaguchi, N., Xu, L., Pasek, D.A., Evans, K.E., Chen, S.R., Meissner, G. Biochemistry (2005) [Pubmed]
  25. The glutathione transferase structural family includes a nuclear chloride channel and a ryanodine receptor calcium release channel modulator. Dulhunty, A., Gage, P., Curtis, S., Chelvanayagam, G., Board, P. J. Biol. Chem. (2001) [Pubmed]
  26. Ryanodine receptors, FKBP12, and heart failure. Marks, A.R. Front. Biosci. (2002) [Pubmed]
  27. Isoform-dependent formation of heteromeric Ca2+ release channels (ryanodine receptors). Xiao, B., Masumiya, H., Jiang, D., Wang, R., Sei, Y., Zhang, L., Murayama, T., Ogawa, Y., Lai, F.A., Wagenknecht, T., Chen, S.R. J. Biol. Chem. (2002) [Pubmed]
  28. A recently identified member of the glutathione transferase structural family modifies cardiac RyR2 substate activity, coupled gating and activation by Ca2+ and ATP. Dulhunty, A.F., Pouliquin, P., Coggan, M., Gage, P.W., Board, P.G. Biochem. J. (2005) [Pubmed]
  29. The human cardiac muscle ryanodine receptor-calcium release channel: identification, primary structure and topological analysis. Tunwell, R.E., Wickenden, C., Bertrand, B.M., Shevchenko, V.I., Walsh, M.B., Allen, P.D., Lai, F.A. Biochem. J. (1996) [Pubmed]
  30. Ryanodine receptor regulation by intramolecular interaction between cytoplasmic and transmembrane domains. George, C.H., Jundi, H., Thomas, N.L., Scoote, M., Walters, N., Williams, A.J., Lai, F.A. Mol. Biol. Cell (2004) [Pubmed]
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