Ryanodine receptor 2 explained

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.^{[1] [2] [3]} 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.^[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 myosin ATPase 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]

Mutations in the RYR2 gene are associated with catecholaminergic polymorphic ventricular tachycardia and arrhythmogenic right ventricular dysplasia.^[8]

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.^[9] 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.^[10]

Interactions

Ryanodine receptor 2 has been shown to interact with:

• Protein kinase A (AKAP6,^[11] PRKACA,^[12] PRKACB,^[12] PRKACG,^[12]) (phosphorylation at serine position S2808 in rodents^[13])
• CaMKII (via phosphorylation at serine positions S2808 and S2814 in humans and rodents, S2809^[14] and S2815^[15] in rabbits)
• SRI^[16]
• Protein phosphatase 1 (dephosphorylation at serine positions S2808 and S2814 in rodents^[17])
• Protein phosphatase 2 (dephosphorylation at serine position S2814 in rodents^[18])

See also

• Ryanodine receptor

Further reading

• Ogawa Y, Kurebayashi N, Murayama T . Ryanodine receptor isoforms in excitation-contraction coupling . Advances in Biophysics . 36 . 27–64 . 1999 . 10463072 . 10.1016/S0065-227X(99)80004-5 .
• Marks AR, Priori S, Memmi M, Kontula K, Laitinen PJ . Involvement of the cardiac ryanodine receptor/calcium release channel in catecholaminergic polymorphic ventricular tachycardia . Journal of Cellular Physiology . 190 . 1 . 1–6 . January 2002 . 11807805 . 10.1002/jcp.10031 . free .
• Marks AR . Ryanodine receptors, FKBP12, and heart failure . Frontiers in Bioscience . 7 . 1–3 . d970-7 . April 2002 . 11897558 . 10.2741/marks . free .
• Danieli GA, Rampazzo A . Genetics of arrhythmogenic right ventricular cardiomyopathy . Current Opinion in Cardiology . 17 . 3 . 218–21 . May 2002 . 12015469 . 10.1097/00001573-200205000-00002 .
• Ma J, Hayek SM, Bhat MB . Membrane topology and membrane retention of the ryanodine receptor calcium release channel . Cell Biochemistry and Biophysics . 40 . 2 . 207–24 . 2005 . 15054223 . 10.1385/CBB:40:2:207 . 25375622 .
• Meyers MB, Pickel VM, Sheu SS, Sharma VK, Scotto KW, Fishman GI . Association of sorcin with the cardiac ryanodine receptor . The Journal of Biological Chemistry . 270 . 44 . 26411–8 . November 1995 . 7592856 . 10.1074/jbc.270.44.26411 . free .
• Rampazzo A, Nava A, Erne P, Eberhard M, Vian E, Slomp P, Tiso N, Thiene G, Danieli GA . 6 . A new locus for arrhythmogenic right ventricular cardiomyopathy (ARVD2) maps to chromosome 1q42-q43 . Human Molecular Genetics . 4 . 11 . 2151–4 . November 1995 . 8589694 . 10.1093/hmg/4.11.2151 .
• Tunwell RE, Wickenden C, Bertrand BM, Shevchenko VI, Walsh MB, Allen PD, Lai FA . The human cardiac muscle ryanodine receptor-calcium release channel: identification, primary structure and topological analysis . The Biochemical Journal . 318 . Pt 2 . 477–87 . September 1996 . 8809036 . 1217646 . 10.1042/bj3180477 .
• Awad SS, Lamb HK, Morgan JM, Dunlop W, Gillespie JI . Differential expression of ryanodine receptor RyR2 mRNA in the non-pregnant and pregnant human myometrium . The Biochemical Journal . 322 . Pt 3 . 777–83 . March 1997 . 9148749 . 1218255 . 10.1042/bj3220777 .
• Martin C, Chapman KE, Seckl JR, Ashley RH . 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 . July 1998 . 9607712 . 10.1016/S0306-4522(97)00612-X . 25634042 .
• Chambers P, Neal DE, Gillespie JI . Ryanodine receptors in human bladder smooth muscle . Experimental Physiology . 84 . 1 . 41–6 . January 1999 . 10081705 . 10.1111/j.1469-445x.1999.tb00070.x . free .
• Mori F, Fukaya M, Abe H, Wakabayashi K, Watanabe M . Developmental changes in expression of the three ryanodine receptor mRNAs in the mouse brain . Neuroscience Letters . 285 . 1 . 57–60 . May 2000 . 10788707 . 10.1016/S0304-3940(00)01046-6 . 32514035 .
• Marx SO, Reiken S, Hisamatsu Y, Jayaraman T, Burkhoff D, Rosemblit N, Marks AR . PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts . Cell . 101 . 4 . 365–76 . May 2000 . 10830164 . 10.1016/S0092-8674(00)80847-8 . 6496567 . free .
• 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 . 6 . Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia . Circulation . 103 . 4 . 485–90 . January 2001 . 11157710 . 10.1161/01.cir.103.4.485 . free . 11577/153951 . free .
• Priori SG, Napolitano C, Tiso N, Memmi M, Vignati G, Bloise R, Sorrentino V, Danieli GA . 6 . Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia . Circulation . 103 . 2 . 196–200 . January 2001 . 11208676 . 10.1161/01.cir.103.2.196 . free .
• Jeyakumar LH, Ballester L, Cheng DS, McIntyre JO, Chang P, Olivey HE, Rollins-Smith L, Barnett JV, Murray K, Xin HB, Fleischer S . 6 . FKBP binding characteristics of cardiac microsomes from diverse vertebrates . Biochemical and Biophysical Research Communications . 281 . 4 . 979–86 . March 2001 . 11237759 . 10.1006/bbrc.2001.4444 .

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

Notes and References

1. 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 . The Journal of Biological Chemistry . 265 . 23 . 13472–83 . August 1990 . 10.1016/S0021-9258(18)77371-7 . 2380170 . free .
2. Otsu K, Fujii J, Periasamy M, Difilippantonio M, Uppender M, Ward DC, MacLennan DH . Chromosome mapping of five human cardiac and skeletal muscle sarcoplasmic reticulum protein genes . Genomics . 17 . 2 . 507–9 . August 1993 . 8406504 . 10.1006/geno.1993.1357 . free .
3. 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 . 6 . 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 . February 2001 . 11159936 . 10.1093/hmg/10.3.189 . free . 11577/2459215 . free .
4. Guo T, Cornea RL, Huke S, Camors E, Yang Y, Picht E, Fruen BR, Bers DM . 6 . Kinetics of FKBP12.6 binding to ryanodine receptors in permeabilized cardiac myocytes and effects on Ca sparks . Circulation Research . 106 . 11 . 1743–52 . June 2010 . 20431056 . 2895429 . 10.1161/CIRCRESAHA.110.219816 .
5. Web site: Q92736 - RYR2_HUMAN.
6. Bround MJ, Wambolt R, Luciani DS, Kulpa JE, Rodrigues B, Brownsey RW, Allard MF, Johnson JD . 6 . 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 . June 2013 . 23678000 . 3696672 . 10.1074/jbc.M112.427062 . free .
7. Belevych AE, Radwański PB, Carnes CA, Györke S . 'Ryanopathy': causes and manifestations of RyR2 dysfunction in heart failure . Cardiovascular Research . 98 . 2 . 240–7 . May 2013 . 23408344 . 3633158 . 10.1093/cvr/cvt024 .
8. Web site: Entrez Gene: RYR2 ryanodine receptor 2 (cardiac).
9. Tester DJ, Bombei HM, Fitzgerald KK, Giudicessi JR, Pitel BA, Thorland EC, Russell BG, Hamrick SK, Kim CS, Haglund-Turnquist CM, Johnsrude CL, Atkins DL, Ochoa Nunez LA, Law I, Temple J, Ackerman MJ . 6 . Identification of a Novel Homozygous Multi-Exon Duplication in RYR2 Among Children With Exertion-Related Unexplained Sudden Deaths in the Amish Community . JAMA Cardiology . January 2020 . 31913406 . 10.1001/jamacardio.2019.5400 . 6990654 . 5 . 3 . 13–18 .
10. Bround MJ, Asghari P, Wambolt RB, Bohunek L, Smits C, Philit M, Kieffer TJ, Lakatta EG, Boheler KR, Moore ED, Allard MF, Johnson JD . 6 . Cardiac ryanodine receptors control heart rate and rhythmicity in adult mice . Cardiovascular Research . 96 . 3 . 372–80 . December 2012 . 22869620 . 3500041 . 10.1093/cvr/cvs260 .
11. Marx SO, Reiken S, Hisamatsu Y, Gaburjakova M, Gaburjakova J, Yang YM, Rosemblit N, Marks AR . 6 . Phosphorylation-dependent regulation of ryanodine receptors: a novel role for leucine/isoleucine zippers . The Journal of Cell Biology . 153 . 4 . 699–708 . May 2001 . 11352932 . 2192391 . 10.1083/jcb.153.4.699 .
12. Marx SO, Reiken S, Hisamatsu Y, Jayaraman T, Burkhoff D, Rosemblit N, Marks AR . PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts . Cell . 101 . 4 . 365–76 . May 2000 . 10830164 . 10.1016/S0092-8674(00)80847-8 . 6496567 . free .
13. 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 . 10.1016/j.bbrc.2008.08.084 . 1090-2104 . 2581610 . 18755143.
14. 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 . 10.1016/S0021-9258(18)99140-4 . free . 0021-9258 . 1645727.
15. 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 . en . 94 . 6 . e61-70 . 10.1161/01.RES.0000125626.33738.E2 . 15016728 . 0009-7330.
16. Meyers MB, Pickel VM, Sheu SS, Sharma VK, Scotto KW, Fishman GI . Association of sorcin with the cardiac ryanodine receptor . The Journal of Biological Chemistry . 270 . 44 . 26411–8 . November 1995 . 7592856 . 10.1074/jbc.270.44.26411 . free .
17. 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 . 10.1016/j.bbrc.2008.08.084 . 1090-2104 . 2581610 . 18755143.
18. 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 . 10.1016/j.bbrc.2008.08.084 . 1090-2104 . 2581610 . 18755143.