RYR2 | |||||||||||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
![]() | |||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
Aliases | RYR2, ARVC2, ARVD2, RYR-2, RyR, VTSIP, ryanodine receptor 2, VACRDS | ||||||||||||||||||||||||||||||||||||||||||||||||||
External IDs | OMIM: 180902; MGI: 99685; HomoloGene: 37423; GeneCards: RYR2; OMA:RYR2 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
|
Ryanodine receptor 2 (RYR2) is one of a class of ryanodine receptors and a protein found primarily in cardiac muscle. In humans, it is encoded by the RYR2 gene.[5][6][7] In the process of cardiac calcium-induced calcium release, RYR2 is the major mediator for sarcoplasmic release of stored calcium ions.
Structure
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.[8]
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 myosin ATPase to bind to actin, enabling cardiac muscle contraction.[9] RYR2 channels are associated with many cellular functions, including mitochondrial metabolism, gene expression and cell survival, in addition to their role in cardiomyocyte contraction.[10]
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."[11]
Mutations in the RYR2 gene are associated with catecholaminergic polymorphic ventricular tachycardia and arrhythmogenic right ventricular dysplasia.[12]
Recently, sudden cardiac death in several young individuals in the Amish community (four of which were from the same family) was traced to homozygous duplication of a mutant RyR2 gene.[13] Normal (wild type) RyR2 functions primarily in the myocardium (heart muscle).
Mice with genetically reduced RYR2 exhibit a lower basal heart rate and fatal arrhythmias.[14]
Interactions
Ryanodine receptor 2 has been shown to interact with:
- Protein kinase A (AKAP6,[15][16] PRKACA,[15] PRKACB,[15] PRKACG,[15]) (phosphorylation at serine position S2808 in rodents[17])
- CaMKII (via phosphorylation at serine positions S2808 and S2814 in humans and rodents, S2809[18] and S2815[19] in rabbits)
- SRI[20]
- Protein phosphatase 1 (dephosphorylation at serine positions S2808 and S2814 in rodents[21])
- Protein phosphatase 2 (dephosphorylation at serine position S2814 in rodents[22])
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000198626 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000021313 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Otsu K, Willard HF, Khanna VK, Zorzato F, Green NM, MacLennan DH (August 1990). "Molecular cloning of cDNA encoding the Ca2+ release channel (ryanodine receptor) of rabbit cardiac muscle sarcoplasmic reticulum". The Journal of Biological Chemistry. 265 (23): 13472–83. doi:10.1016/S0021-9258(18)77371-7. PMID 2380170.
- ^ Otsu K, Fujii J, Periasamy M, Difilippantonio M, Uppender M, Ward DC, MacLennan DH (August 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. PMID 8406504.
- ^ Tiso N, Stephan DA, Nava A, Bagattin A, Devaney JM, Stanchi F, et al. (February 2001). "Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2)". Human Molecular Genetics. 10 (3): 189–94. doi:10.1093/hmg/10.3.189. hdl:11577/2459215. PMID 11159936.
- ^ Guo T, Cornea RL, Huke S, Camors E, Yang Y, Picht E, et al. (June 2010). "Kinetics of FKBP12.6 binding to ryanodine receptors in permeabilized cardiac myocytes and effects on Ca sparks". Circulation Research. 106 (11): 1743–52. doi:10.1161/CIRCRESAHA.110.219816. PMC 2895429. PMID 20431056.
- ^ "Q92736 - RYR2_HUMAN".
- ^ Bround MJ, Wambolt R, Luciani DS, Kulpa JE, Rodrigues B, Brownsey RW, et al. (June 2013). "Cardiomyocyte ATP production, metabolic flexibility, and survival require calcium flux through cardiac ryanodine receptors in vivo". The Journal of Biological Chemistry. 288 (26): 18975–86. doi:10.1074/jbc.M112.427062. PMC 3696672. PMID 23678000.
- ^ Belevych AE, Radwański PB, Carnes CA, Györke S (May 2013). "'Ryanopathy': causes and manifestations of RyR2 dysfunction in heart failure". Cardiovascular Research. 98 (2): 240–7. doi:10.1093/cvr/cvt024. PMC 3633158. PMID 23408344.
- ^ "Entrez Gene: RYR2 ryanodine receptor 2 (cardiac)".
- ^ Tester DJ, Bombei HM, Fitzgerald KK, Giudicessi JR, Pitel BA, Thorland EC, et al. (January 2020). "Identification of a Novel Homozygous Multi-Exon Duplication in RYR2 Among Children With Exertion-Related Unexplained Sudden Deaths in the Amish Community". JAMA Cardiology. 5 (3): 13–18. doi:10.1001/jamacardio.2019.5400. PMC 6990654. PMID 31913406.
- ^ Bround MJ, Asghari P, Wambolt RB, Bohunek L, Smits C, Philit M, et al. (December 2012). "Cardiac ryanodine receptors control heart rate and rhythmicity in adult mice". Cardiovascular Research. 96 (3): 372–80. doi:10.1093/cvr/cvs260. PMC 3500041. PMID 22869620.
- ^ a b c d Marx 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. PMID 10830164. S2CID 6496567.
- ^ Marx SO, Reiken S, Hisamatsu Y, Gaburjakova M, Gaburjakova J, Yang YM, et al. (May 2001). "Phosphorylation-dependent regulation of ryanodine receptors: a novel role for leucine/isoleucine zippers". The Journal of Cell Biology. 153 (4): 699–708. doi:10.1083/jcb.153.4.699. PMC 2192391. PMID 11352932.
- ^ Huke, Sabine; Bers, Donald M. (2008-11-07). "Ryanodine receptor phosphorylation at Serine 2030, 2808 and 2814 in rat cardiomyocytes". Biochemical and Biophysical Research Communications. 376 (1): 80–85. doi:10.1016/j.bbrc.2008.08.084. ISSN 1090-2104. PMC 2581610. PMID 18755143.
- ^ Witcher, D. R.; Kovacs, R. J.; Schulman, H.; Cefali, D. C.; Jones, L. R. (1991-06-15). "Unique phosphorylation site on the cardiac ryanodine receptor regulates calcium channel activity". The Journal of Biological Chemistry. 266 (17): 11144–11152. doi:10.1016/S0021-9258(18)99140-4. ISSN 0021-9258. PMID 1645727.
- ^ Wehrens, Xander H.T.; Lehnart, Stephan E.; Reiken, Steven R.; Marks, Andrew R. (2004-04-02). "Ca 2+ /Calmodulin-Dependent Protein Kinase II Phosphorylation Regulates the Cardiac Ryanodine Receptor". Circulation Research. 94 (6): e61-70. doi:10.1161/01.RES.0000125626.33738.E2. ISSN 0009-7330. PMID 15016728.
- ^ Meyers MB, Pickel VM, Sheu SS, Sharma VK, Scotto KW, Fishman GI (November 1995). "Association of sorcin with the cardiac ryanodine receptor". The Journal of Biological Chemistry. 270 (44): 26411–8. doi:10.1074/jbc.270.44.26411. PMID 7592856.
- ^ Huke, Sabine; Bers, Donald M. (2008-11-07). "Ryanodine receptor phosphorylation at Serine 2030, 2808 and 2814 in rat cardiomyocytes". Biochemical and Biophysical Research Communications. 376 (1): 80–85. doi:10.1016/j.bbrc.2008.08.084. ISSN 1090-2104. PMC 2581610. PMID 18755143.
- ^ Huke, Sabine; Bers, Donald M. (2008-11-07). "Ryanodine receptor phosphorylation at Serine 2030, 2808 and 2814 in rat cardiomyocytes". Biochemical and Biophysical Research Communications. 376 (1): 80–85. doi:10.1016/j.bbrc.2008.08.084. ISSN 1090-2104. PMC 2581610. PMID 18755143.
Further reading
- Ogawa Y, Kurebayashi N, Murayama T (1999). "Ryanodine receptor isoforms in excitation-contraction coupling". Advances in Biophysics. 36: 27–64. doi:10.1016/S0065-227X(99)80004-5. PMID 10463072.
- Marks AR, Priori S, Memmi M, Kontula K, Laitinen PJ (January 2002). "Involvement of the cardiac ryanodine receptor/calcium release channel in catecholaminergic polymorphic ventricular tachycardia". Journal of Cellular Physiology. 190 (1): 1–6. doi:10.1002/jcp.10031. PMID 11807805.
- Marks AR (April 2002). "Ryanodine receptors, FKBP12, and heart failure". Frontiers in Bioscience. 7 (1–3): d970-7. doi:10.2741/marks. PMID 11897558.
- Danieli GA, Rampazzo A (May 2002). "Genetics of arrhythmogenic right ventricular cardiomyopathy". Current Opinion in Cardiology. 17 (3): 218–21. doi:10.1097/00001573-200205000-00002. PMID 12015469.
- Ma J, Hayek SM, Bhat MB (2005). "Membrane topology and membrane retention of the ryanodine receptor calcium release channel". Cell Biochemistry and Biophysics. 40 (2): 207–24. doi:10.1385/CBB:40:2:207. PMID 15054223. S2CID 25375622.
- Meyers MB, Pickel VM, Sheu SS, Sharma VK, Scotto KW, Fishman GI (November 1995). "Association of sorcin with the cardiac ryanodine receptor". The Journal of Biological Chemistry. 270 (44): 26411–8. doi:10.1074/jbc.270.44.26411. PMID 7592856.
- Rampazzo A, Nava A, Erne P, Eberhard M, Vian E, Slomp P, et al. (November 1995). "A new locus for arrhythmogenic right ventricular cardiomyopathy (ARVD2) maps to chromosome 1q42-q43" (PDF). Human Molecular Genetics. 4 (11): 2151–4. doi:10.1093/hmg/4.11.2151. PMID 8589694.
- Tunwell RE, Wickenden C, Bertrand BM, Shevchenko VI, Walsh MB, Allen PD, Lai FA (September 1996). "The human cardiac muscle ryanodine receptor-calcium release channel: identification, primary structure and topological analysis". The Biochemical Journal. 318 (Pt 2): 477–87. doi:10.1042/bj3180477. PMC 1217646. PMID 8809036.
- Awad SS, Lamb HK, Morgan JM, Dunlop W, Gillespie JI (March 1997). "Differential expression of ryanodine receptor RyR2 mRNA in the non-pregnant and pregnant human myometrium". The Biochemical Journal. 322 (Pt 3): 777–83. doi:10.1042/bj3220777. PMC 1218255. PMID 9148749.
- Martin C, Chapman KE, Seckl JR, Ashley RH (July 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. PMID 9607712. S2CID 25634042.
- Chambers P, Neal DE, Gillespie JI (January 1999). "Ryanodine receptors in human bladder smooth muscle". Experimental Physiology. 84 (1): 41–6. doi:10.1111/j.1469-445x.1999.tb00070.x. PMID 10081705.
- Mori F, Fukaya M, Abe H, Wakabayashi K, Watanabe M (May 2000). "Developmental changes in expression of the three ryanodine receptor mRNAs in the mouse brain". Neuroscience Letters. 285 (1): 57–60. doi:10.1016/S0304-3940(00)01046-6. PMID 10788707. S2CID 32514035.
- Marx 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. PMID 10830164. S2CID 6496567.
- Laitinen PJ, Brown KM, Piippo K, Swan H, Devaney JM, Brahmbhatt B, et al. (January 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. hdl:11577/153951. PMID 11157710.
- Priori SG, Napolitano C, Tiso N, Memmi M, Vignati G, Bloise R, et al. (January 2001). "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. PMID 11208676.
- Jeyakumar LH, Ballester L, Cheng DS, McIntyre JO, Chang P, Olivey HE, et al. (March 2001). "FKBP binding characteristics of cardiac microsomes from diverse vertebrates". Biochemical and Biophysical Research Communications. 281 (4): 979–86. doi:10.1006/bbrc.2001.4444. PMID 11237759.
External links
- GeneReviews/NCBI/NIH/UW entry on Catecholaminergic Polymorphic Ventricular Tachycardia
- GeneReviews/NCBI/NIH/UW entry on Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autosomal Dominant
- OMIM entries on Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autosomal Dominant
- RYR2+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)