Ryanodine receptor 2

RYR2
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	4JKQ
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
Gene location (Human)
Chr.	Chromosome 1 (human)
End	237,833,988 bp
Gene location (Mouse)
Chr.	Chromosome 13 (mouse)
End	12,106,945 bp
RNA expression pattern
	Top expressed in
	right ventricle; ; myocardium of left ventricle; ; cardiac muscle tissue of right atrium; ; apex of heart; ; right auricle; ; endothelial cell; ; Brodmann area 23; ; vena cava; ; primary visual cortex; ; right hemisphere of cerebellum;
	Top expressed in
	myocardium of ventricle; ; cardiac muscle tissue of left ventricle; ; right ventricle; ; interventricular septum; ; atrium; ; atrioventricular valve; ; lateral septal nucleus; ; dentate gyrus; ; primary motor cortex; ; anterior amygdaloid area;
	More reference expression data
	n/a
Gene ontology
Molecular function	transmembrane transporter binding; calcium channel activity; calcium-induced calcium release activity; protein kinase A catalytic subunit binding; organic cyclic compound binding; protein self-association; ion channel activity; protein binding; identical protein binding; enzyme binding; suramin binding; protein kinase A regulatory subunit binding; protein kinase binding; calcium-release channel activity; ryanodine-sensitive calcium-release channel activity; calcium ion binding; calmodulin binding;
Cellular component	integral component of membrane; calcium channel complex; membrane; sarcomere; junctional sarcoplasmic reticulum membrane; sarcoplasmic reticulum; Z discdkac; sarcoplasmic reticulum membrane; smooth endoplasmic reticulum; plasma membrane; protein-containing complex; cytoplasmic vesicle membrane; sarcolemma;
Biological process	response to muscle stretch; release of sequestered calcium ion into cytosol; calcium ion transport into cytosol; regulation of cardiac conduction; regulation of cardiac muscle contraction by calcium ion signaling; release of sequestered calcium ion into cytosol by sarcoplasmic reticulum; response to hypoxia; cardiac muscle contraction; regulation of cytosolic calcium ion concentration; positive regulation of the force of heart contraction; regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion; cardiac muscle hypertrophy; ventricular cardiac muscle cell action potential; cell communication by electrical coupling involved in cardiac conduction; cellular calcium ion homeostasis; establishment of protein localization to endoplasmic reticulum; ion transport; BMP signaling pathway; left ventricular cardiac muscle tissue morphogenesis; regulation of heart rate; positive regulation of heart rate; detection of calcium ion; response to redox state; cellular response to epinephrine stimulus; multicellular organism development; ion transmembrane transport; positive regulation of sequestering of calcium ion; embryonic heart tube morphogenesis; calcium ion transmembrane transport; cellular response to caffeine; sarcoplasmic reticulum calcium ion transport; canonical Wnt signaling pathway; regulation of SA node cell action potential; response to caffeine; regulation of cardiac muscle contraction; regulation of ventricular cardiac muscle cell action potential; regulation of AV node cell action potential; calcium-mediated signaling using intracellular calcium source; response to muscle activity; calcium ion transport; calcium-mediated signaling; type B pancreatic cell apoptotic process; regulation of atrial cardiac muscle cell action potential; positive regulation of ATPase-coupled calcium transmembrane transporter activity; Purkinje myocyte to ventricular cardiac muscle cell signaling; transmembrane transport;
	Sources:Amigo / QuickGO
Orthologs
	6262
	20191
	ENSG00000198626
	ENSMUSG00000021313
	Q92736
	E9Q401
	NM_001035
	NM_023868
	NP_001026
	NP_076357
	Wikidata
View/Edit Human	View/Edit Mouse

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^[17])
Protein phosphatase 2 (dephosphorylation at serine position S2814 in rodents<ref name = "Huke_2008" / >)

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): 13472–13483. doi:10.1016/S0021-9258(18)77371-7. PMID 2380170.
^ Otsu K, Fujii J, Periasamy M, Difilippantonio M, Uppender M, Ward DC, et al. (August 1993). "Chromosome mapping of five human cardiac and skeletal muscle sarcoplasmic reticulum protein genes". Genomics. 17 (2): 507–509. 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): 189–194. 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): 1743–1752. 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): 18975–18986. 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): 240–247. 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. (March 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): 372–380. 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, et al. (May 2000). "PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts". Cell. 101 (4): 365–376. 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.
^ ^a ^b Huke S, Bers DM (November 2008). "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. PMC 2581610. PMID 18755143.
^ Witcher DR, Kovacs RJ, Schulman H, Cefali DC, Jones LR (June 1991). "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. PMID 1645727.
^ Wehrens XH, Lehnart SE, Reiken SR, Marks AR (April 2004). "Ca2+/calmodulin-dependent protein kinase II phosphorylation regulates the cardiac ryanodine receptor". Circulation Research. 94 (6): e61–e70. doi:10.1161/01.RES.0000125626.33738.E2. 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): 26411–26418. doi:10.1074/jbc.270.44.26411. PMID 7592856.

External links

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000198626 – Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000021313 – Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid2380170-5] 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): 13472–13483. doi:10.1016/S0021-9258(18)77371-7. PMID 2380170.

[pmid8406504-6] Otsu K, Fujii J, Periasamy M, Difilippantonio M, Uppender M, Ward DC, et al. (August 1993). "Chromosome mapping of five human cardiac and skeletal muscle sarcoplasmic reticulum protein genes". Genomics. 17 (2): 507–509. doi:10.1006/geno.1993.1357. PMID 8406504.

[pmid11159936-7] 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): 189–194. doi:10.1093/hmg/10.3.189. hdl:11577/2459215. PMID 11159936.

[pmid204310562-8] 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): 1743–1752. doi:10.1161/CIRCRESAHA.110.219816. PMC 2895429. PMID 20431056.

[Uniprot2-9] "Q92736 - RYR2_HUMAN".

[10] 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): 18975–18986. doi:10.1074/jbc.M112.427062. PMC 3696672. PMID 23678000.

[pmid23408344-11] Belevych AE, Radwański PB, Carnes CA, Györke S (May 2013). "'Ryanopathy': causes and manifestations of RyR2 dysfunction in heart failure". Cardiovascular Research. 98 (2): 240–247. doi:10.1093/cvr/cvt024. PMC 3633158. PMID 23408344.

[entrez-12] "Entrez Gene: RYR2 ryanodine receptor 2 (cardiac)".

[13] Tester DJ, Bombei HM, Fitzgerald KK, Giudicessi JR, Pitel BA, Thorland EC, et al. (March 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.

[pmid22869620-14] 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): 372–380. doi:10.1093/cvr/cvs260. PMC 3500041. PMID 22869620.

[pmid10830164-15] Marx SO, Reiken S, Hisamatsu Y, Jayaraman T, Burkhoff D, Rosemblit N, et al. (May 2000). "PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts". Cell. 101 (4): 365–376. doi:10.1016/S0092-8674(00)80847-8. PMID 10830164. S2CID 6496567.

[pmid11352932-16] 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_2008-17] Huke S, Bers DM (November 2008). "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. PMC 2581610. PMID 18755143.

[18] Witcher DR, Kovacs RJ, Schulman H, Cefali DC, Jones LR (June 1991). "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. PMID 1645727.

[19] Wehrens XH, Lehnart SE, Reiken SR, Marks AR (April 2004). "Ca2+/calmodulin-dependent protein kinase II phosphorylation regulates the cardiac ryanodine receptor". Circulation Research. 94 (6): e61–e70. doi:10.1161/01.RES.0000125626.33738.E2. PMID 15016728.

[pmid7592856-20] 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): 26411–26418. doi:10.1074/jbc.270.44.26411. PMID 7592856.

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