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Gene Review

RYR1  -  ryanodine receptor 1 (skeletal)

Homo sapiens

Synonyms: CCO, MHS, MHS1, PPP1R137, RYDR, ...
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Disease relevance of RYR1


Psychiatry related information on RYR1


High impact information on RYR1

  • The RyR channels are ubiquitously expressed in many types of cells and participate in a variety of important Ca2+ signaling phenomena (neurotransmission, secretion, etc.). In striated muscle, the RyR channels represent the primary pathway for Ca2+ release during the excitation-contraction coupling process [11].
  • Skeletal and cardiac muscles contain different RyR and DHPR isoforms and both contribute to the diversity in cardiac and skeletal excitation-contraction coupling mechanisms [12].
  • The ryanodine receptor (RyR) is a high-conductance Ca2+ channel of the sarcoplasmic reticulum in muscle and of the endoplasmic reticulum in other cells [12].
  • The effects of caffeine and anesthetic agents on MHS and normal muscle are also discussed to better understand the basis for the in vitro clinical test for this disorder and mechanisms responsible for the initiation and maintenance of MH episodes in susceptible individuals [13].
  • Although RYR1 mutations have been reported in many MHS human families, there is also significant genetic heterogeneity, and much less is known as to the underlying mechanism responsible for altered human myoplasmic Ca2+ regulation [13].

Chemical compound and disease context of RYR1


Biological context of RYR1

  • RYR1 was consequently postulated as the candidate for the molecular defect causing MHS, and a point mutation in the gene has now been identified and is thought to be the cause of MH in at least some MHS patients [1].
  • In these families, pairwise and multipoint lod scores below -2 exclude MHS from an interval spanning more than 26 cM and comprising the RYR1 and the previously described MHS locus [1].
  • In the second family only one informative meiosis was seen with RYR1 [1].
  • In the 109 individuals of the 25 families with RYR1 mutations cosegregation between genetic result and IVCT was almost perfect, only three genotypes were discordant with the IVCT phenotypes, suggesting a true sensitivity of 98.5% and a specificity of minimally 81.8% for this test [19].
  • Missense mutations in the skeletal muscle ryanodine receptor gene (RYR1) have been identified in some families with CCD [20].

Anatomical context of RYR1


Associations of RYR1 with chemical compounds

  • Correlation analysis of the in vitro contracture-test data available for pedigrees bearing these and other RYR1 mutations showed an exceptionally good correlation between caffeine threshold and tension values, whereas no correlation was observed between halothane threshold and tension values [25].
  • Expression of the mutant RYR1 cDNA produced channels with increased caffeine sensitivity and a significantly reduced maximal level of Ca(2+) release [20].
  • According to a four-transmembrane domain model, the mutations concentrated mostly in the myoplasmic and luminal loops linking, respectively, transmembrane domains T1 and T2 or T3 and T4 of RYR1 [26].
  • DNA sequencing identified a T to C transition at nucleotide position 103, resulting in the substitution of an arginine for cysteine 35, representing the most N-terminal mutation reported to date in the RYR1 gene [27].
  • We have screened the RYR1 gene in affected individuals for novel MHS mutations by single stranded conformational polymorphism (SSCP) analysis and have identified a G to T transition mutation which results in the replacement of a conserved arginine (Arg) at position 614 with a leucine (Leu) [28].
  • The MH-triggering agent, halothane, potentiated the response of RyR1 to luminal Ca(2+) and SOICR [29].

Physical interactions of RYR1

  • Structural differences in the FKBP-binding site of RyRs and IP(3)Rs may contribute to the occurrence of a stable interaction between RyR isoforms and FKBPs and to the absence of such interaction with IP(3)Rs [30].
  • Ryanodine receptor binding of snapin is not isoform specific and is conserved in homologous RyR1 and RyR3 fragments [31].
  • We also found that a distinct, alternatively spliced variant of FKBP12.6 was unable to interact with RyR [32].
  • The CASQ2 protein serves as the major Ca(2+) reservoir within the SR of cardiac myocytes and is part of a protein complex that contains the ryanodine receptor [33].
  • The results show that CLIC-2 interacts with the RyR protein by a mechanism that does not require oxidation, but is influenced by a conserved Cys residue at position 30 [34].

Co-localisations of RYR1


Regulatory relationships of RYR1

  • Interestingly, myotubes expressing RyR3 always had significantly higher [Ca(2+)](r) and lower caffeine EC(50) than did cells expressing RyR1 [15].
  • The role of prolyl isomerase activity of FKBP in regulating RyR function remains uncertain, and several models have been proposed that could explain how the channel is modulated by its association with FKBP [36].
  • Taken together, these results suggest that abnormal release of calcium via mutated RYR enhances the production of the inflammatory cytokine IL-6, which may in turn affect signaling pathways responsible for the trophic status of muscle fibers [2].
  • High activity skeletal RyR1 channels were inactivated at positive potentials or activated at negative potentials by hGSTM2-2 (8-30muM) [37].
  • Based on these data, we conclude that expression of TRPC3 is tightly regulated during muscle cell differentiation and propose that functional interaction between TRPC3 and RyR1 may regulate the gain of SR Ca(2+) release independent of SR Ca(2+) load [38].

Other interactions of RYR1

  • The RyR2 mutations detected in the present study occurred in two highly conserved regions, strictly corresponding to those where mutations causing MH or CCD are clustered in the RYR1 gene [39].
  • We recently identified a novel marker within the gamma-subunit locus (CACNLG) at band 17q24, and since both markers are within the 17q11.2-q24 region reported to contain the MHS2 locus, we tested them for linkage in MHS families whose disease trait has been shown not to co-segregate with markers for the RYR1 region on chromosome 19q13 [40].
  • For both RyRs, the stoichiometry is 4 FKBP/RyR [41].
  • Interaction of FKBP12.6 with the cardiac ryanodine receptor C-terminal domain [42].
  • The ryanodine receptor-calcium release channel complex (RyR) plays a pivotal role in excitation-contraction coupling in skeletal and cardiac muscle [42].

Analytical, diagnostic and therapeutic context of RYR1


  1. Evidence for genetic heterogeneity of malignant hyperthermia susceptibility. Deufel, T., Golla, A., Iles, D., Meindl, A., Meitinger, T., Schindelhauer, D., DeVries, A., Pongratz, D., MacLennan, D.H., Johnson, K.J. Am. J. Hum. Genet. (1992) [Pubmed]
  2. Effect of ryanodine receptor mutations on interleukin-6 release and intracellular calcium homeostasis in human myotubes from malignant hyperthermia-susceptible individuals and patients affected by central core disease. Ducreux, S., Zorzato, F., Müller, C., Sewry, C., Muntoni, F., Quinlivan, R., Restagno, G., Girard, T., Treves, S. J. Biol. Chem. (2004) [Pubmed]
  3. Autosomal recessive inheritance of RYR1 mutations in a congenital myopathy with cores. Jungbluth, H., Müller, C.R., Halliger-Keller, B., Brockington, M., Brown, S.C., Feng, L., Chattopadhyay, A., Mercuri, E., Manzur, A.Y., Ferreiro, A., Laing, N.G., Davis, M.R., Roper, H.P., Dubowitz, V., Bydder, G., Sewry, C.A., Muntoni, F. Neurology (2002) [Pubmed]
  4. Principal mutation hotspot for central core disease and related myopathies in the C-terminal transmembrane region of the RYR1 gene. Davis, M.R., Haan, E., Jungbluth, H., Sewry, C., North, K., Muntoni, F., Kuntzer, T., Lamont, P., Bankier, A., Tomlinson, P., Sánchez, A., Walsh, P., Nagarajan, L., Oley, C., Colley, A., Gedeon, A., Quinlivan, R., Dixon, J., James, D., Müller, C.R., Laing, N.G. Neuromuscul. Disord. (2003) [Pubmed]
  5. Malignant hyperthermia associated with exercise-induced rhabdomyolysis or congenital abnormalities and a novel RYR1 mutation in New Zealand and Australian pedigrees. Davis, M., Brown, R., Dickson, A., Horton, H., James, D., Laing, N., Marston, R., Norgate, M., Perlman, D., Pollock, N., Stowell, K. British journal of anaesthesia. (2002) [Pubmed]
  6. Ryanodine receptor modulation of in vitro associative learning in Hermissenda crassicornis. Blackwell, K.T., Alkon, D.L. Brain Res. (1999) [Pubmed]
  7. Role of ryanodine receptor mutations in cardiac pathology: more questions than answers? Thomas, N.L., George, C.H., Lai, F.A. Biochem. Soc. Trans. (2006) [Pubmed]
  8. Quality of life outcomes of saquinavir, zalcitabine and combination saquinavir plus zalcitabine therapy for adults with advanced HIV infection with CD4 counts between 50 and 300 cells/mm3. Revicki, D.A., Swartz, C., Wu, A.W., Haubrich, R., Collier, A.C. Antivir. Ther. (Lond.) (1999) [Pubmed]
  9. The formation mechanism of a textured ceramic of thermoelectric [Ca2CoO3](0.62)[CoO2] on beta-Co(OH)2 templates through in situ topotactic conversion. Itahara, H., Seo, W.S., Lee, S., Nozaki, H., Tani, T., Koumoto, K. J. Am. Chem. Soc. (2005) [Pubmed]
  10. Alterations in the ryanodine receptor calcium release channel correlate with Alzheimer's disease neurofibrillary and beta-amyloid pathologies. Kelliher, M., Fastbom, J., Cowburn, R.F., Bonkale, W., Ohm, T.G., Ravid, R., Sorrentino, V., O'Neill, C. Neuroscience (1999) [Pubmed]
  11. Ryanodine receptor calcium release channels. Fill, M., Copello, J.A. Physiol. Rev. (2002) [Pubmed]
  12. Ryanodine receptors of striated muscles: a complex channel capable of multiple interactions. Franzini-Armstrong, C., Protasi, F. Physiol. Rev. (1997) [Pubmed]
  13. Malignant hyperthermia: excitation-contraction coupling, Ca2+ release channel, and cell Ca2+ regulation defects. Mickelson, J.R., Louis, C.F. Physiol. Rev. (1996) [Pubmed]
  14. 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]
  15. Expression levels of RyR1 and RyR3 control resting free Ca2+ in skeletal muscle. Perez, C.F., López, J.R., Allen, P.D. Am. J. Physiol., Cell Physiol. (2005) [Pubmed]
  16. Detection of a novel mutation in the ryanodine receptor gene in an Irish malignant hyperthermia pedigree: correlation of the IVCT response with the affected and unaffected haplotypes. Keating, K.E., Giblin, L., Lynch, P.J., Quane, K.A., Lehane, M., Heffron, J.J., McCarthy, T.V. J. Med. Genet. (1997) [Pubmed]
  17. 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]
  18. A substitution of cysteine for arginine 614 in the ryanodine receptor is potentially causative of human malignant hyperthermia. Gillard, E.F., Otsu, K., Fujii, J., Khanna, V.K., de Leon, S., Derdemezi, J., Britt, B.A., Duff, C.L., Worton, R.G., MacLennan, D.H. Genomics (1991) [Pubmed]
  19. Screening of the ryanodine receptor gene in 105 malignant hyperthermia families: novel mutations and concordance with the in vitro contracture test. Brandt, A., Schleithoff, L., Jurkat-Rott, K., Klingler, W., Baur, C., Lehmann-Horn, F. Hum. Mol. Genet. (1999) [Pubmed]
  20. An autosomal dominant congenital myopathy with cores and rods is associated with a neomutation in the RYR1 gene encoding the skeletal muscle ryanodine receptor. Monnier, N., Romero, N.B., Lerale, J., Nivoche, Y., Qi, D., MacLennan, D.H., Fardeau, M., Lunardi, J. Hum. Mol. Genet. (2000) [Pubmed]
  21. Exclusion of malignant hyperthermia susceptibility (MHS) from a putative MHS2 locus on chromosome 17q and of the alpha 1, beta 1, and gamma subunits of the dihydropyridine receptor calcium channel as candidates for the molecular defect. Sudbrak, R., Golla, A., Hogan, K., Powers, P., Gregg, R., Du Chesne, I., Lehmann-Horn, F., Deufel, T. Hum. Mol. Genet. (1993) [Pubmed]
  22. B-lymphocytes from malignant hyperthermia-susceptible patients have an increased sensitivity to skeletal muscle ryanodine receptor activators. Girard, T., Cavagna, D., Padovan, E., Spagnoli, G., Urwyler, A., Zorzato, F., Treves, S. J. Biol. Chem. (2001) [Pubmed]
  23. 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]
  24. The ryanodine receptor/calcium channel genes are widely and differentially expressed in murine brain and peripheral tissues. Giannini, G., Conti, A., Mammarella, S., Scrobogna, M., Sorrentino, V. J. Cell Biol. (1995) [Pubmed]
  25. Identification of novel mutations in the ryanodine-receptor gene (RYR1) in malignant hyperthermia: genotype-phenotype correlation. Manning, B.M., Quane, K.A., Ording, H., Urwyler, A., Tegazzin, V., Lehane, M., O'Halloran, J., Hartung, E., Giblin, L.M., Lynch, P.J., Vaughan, P., Censier, K., Bendixen, D., Comi, G., Heytens, L., Monsieurs, K., Fagerlund, T., Wolz, W., Heffron, J.J., Muller, C.R., McCarthy, T.V. Am. J. Hum. Genet. (1998) [Pubmed]
  26. Familial and sporadic forms of central core disease are associated with mutations in the C-terminal domain of the skeletal muscle ryanodine receptor. Monnier, N., Romero, N.B., Lerale, J., Landrieu, P., Nivoche, Y., Fardeau, M., Lunardi, J. Hum. Mol. Genet. (2001) [Pubmed]
  27. Identification of heterozygous and homozygous individuals with the novel RYR1 mutation Cys35Arg in a large kindred. Lynch, P.J., Krivosic-Horber, R., Reyford, H., Monnier, N., Quane, K., Adnet, P., Haudecoeur, G., Krivosic, I., McCarthy, T., Lunardi, J. Anesthesiology (1997) [Pubmed]
  28. Detection of a novel mutation at amino acid position 614 in the ryanodine receptor in malignant hyperthermia. Quane, K.A., Ording, H., Keating, K.E., Manning, B.M., Heine, R., Bendixen, D., Berg, K., Krivosic-Horber, R., Lehmann-Horn, F., Fagerlund, T., McCarthy, T.V. British journal of anaesthesia. (1997) [Pubmed]
  29. Reduced threshold for luminal Ca2+ activation of RyR1 underlies a causal mechanism of porcine malignant hyperthermia. Jiang, D., Chen, W., Xiao, J., Wang, R., Kong, H., Jones, P.P., Zhang, L., Fruen, B., Chen, S.R. J. Biol. Chem. (2008) [Pubmed]
  30. 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]
  31. Ryanodine receptor interaction with the SNARE-associated protein snapin. Zissimopoulos, S., West, D.J., Williams, A.J., Lai, F.A. J. Cell. Sci. (2006) [Pubmed]
  32. Central domain of the human cardiac muscle ryanodine receptor does not mediate interaction with FKBP12.6. Zissimopoulos, S., Lai, F.A. Cell Biochem. Biophys. (2005) [Pubmed]
  33. 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. 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. Am. J. Hum. Genet. (2001) [Pubmed]
  34. 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]
  35. Functional interaction of the cytoplasmic domain of triadin with the skeletal ryanodine receptor. Groh, S., Marty, I., Ottolia, M., Prestipino, G., Chapel, A., Villaz, M., Ronjat, M. J. Biol. Chem. (1999) [Pubmed]
  36. Intracellular calcium-release channels: regulators of cell life and death. Marks, A.R. Am. J. Physiol. (1997) [Pubmed]
  37. The Mu class glutathione transferase is abundant in striated muscle and is an isoform-specific regulator of ryanodine receptor calcium channels. Abdellatif, Y., Liu, D., Gallant, E.M., Gage, P.W., Board, P.G., Dulhunty, A.F. Cell Calcium (2007) [Pubmed]
  38. Functional coupling between TRPC3 and RyR1 regulates the expressions of key triadic proteins. Lee, E.H., Cherednichenko, G., Pessah, I.N., Allen, P.D. J. Biol. Chem. (2006) [Pubmed]
  39. 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]
  40. Genetic mapping of the beta 1- and gamma-subunits of the human skeletal muscle L-type voltage-dependent calcium channel on chromosome 17q and exclusion as candidate genes for malignant hyperthermia susceptibility. Iles, D.E., Segers, B., Sengers, R.C., Monsieurs, K., Heytens, L., Halsall, P.J., Hopkins, P.M., Ellis, F.R., Hall-Curran, J.L., Stewart, A.D. Hum. Mol. Genet. (1993) [Pubmed]
  41. Three amino acid residues determine selective binding of FK506-binding protein 12.6 to the cardiac ryanodine receptor. Xin, H.B., Rogers, K., Qi, Y., Kanematsu, T., Fleischer, S. J. Biol. Chem. (1999) [Pubmed]
  42. Interaction of FKBP12.6 with the cardiac ryanodine receptor C-terminal domain. Zissimopoulos, S., Lai, F.A. J. Biol. Chem. (2005) [Pubmed]
  43. Ryanodine receptor oligomeric interaction: identification of a putative binding region. Blayney, L.M., Zissimopoulos, S., Ralph, E., Abbot, E., Matthews, L., Lai, F.A. J. Biol. Chem. (2004) [Pubmed]
  44. Expression of ryanodine receptor type 3 and TRP channels in endothelial cells: comparison of in situ and cultured human endothelial cells. Köhler, R., Brakemeier, S., Kühn, M., Degenhardt, C., Buhr, H., Pries, A., Hoyer, J. Cardiovasc. Res. (2001) [Pubmed]
  45. Characterization and mapping of the 12 kDa FK506-binding protein (FKBP12)-binding site on different isoforms of the ryanodine receptor and of the inositol 1,4,5-trisphosphate receptor. Bultynck, G., De Smet, P., Rossi, D., Callewaert, G., Missiaen, L., Sorrentino, V., De Smedt, H., Parys, J.B. Biochem. J. (2001) [Pubmed]
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