Ryanodine receptor 2

Transport protein and coding gene in humans

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

Gene location (Human)

Chr.	Chromosome 1 (human)^[1]

Band	1q43	Start	237,042,184 bp^[1]
Band	1q43	End	237,833,988 bp^[1]

Gene location (Mouse)

Chr.	Chromosome 13 (mouse)^[2]

Band	13 A1\|13 4.38 cM	Start	11,553,102 bp^[2]
Band	13 A1\|13 4.38 cM	End	12,106,945 bp^[2]

RNA expression pattern

Bgee

Human

Mouse (ortholog)

Top expressed in

right ventricle

endothelial cell

Brodmann area 23

vena cava

right coronary artery

orbitofrontal cortex

postcentral gyrus

popliteal artery

superior frontal gyrus

middle temporal gyrus

Top expressed in

myocardium of ventricle

right ventricle

interventricular septum

atrium

atrioventricular valve

dentate gyrus

primary motor cortex

cingulate gyrus

prefrontal cortex

hippocampus proper

More reference expression data

BioGPS

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 disc 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

Species

Human

Mouse

Entrez


6262


20191

Ensembl


ENSG00000198626


ENSMUSG00000021313

UniProt


Q92736


E9Q401

RefSeq (mRNA)


NM_001035


NM_023868

RefSeq (protein)


NP_001026


NP_076357

Location (UCSC)

Chr 1: 237.04 – 237.83 Mb

Chr 13: 11.55 – 12.11 Mb

PubMed search

^[3]

^[4]

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:

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. 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.
^ 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.

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)

Membrane transport protein: ion channels (TC 1A)

Ca²⁺: Calcium channel

Ligand-gated	Inositol trisphosphate receptor 1 2 3 Ryanodine receptor 1 2 3
Voltage-gated	L-type/Ca_vα 1.1 1.2 1.3 1.4 N-type/Ca_vα2.2 P-type/Ca_vα 2.1 Q-type/Ca_vα2.1 R-type/Ca_vα2.3 T-type/Ca_vα 3.1 3.2 3.3 α₂δ-subunits 1 2 β-subunits β1 β2 β3 β4 γ-subunits γ1 γ2 γ3 γ4 Cation channels of sperm 1 2 3 4 Two-pore channel 1 2

Na⁺: Sodium channel

Constitutively active	Epithelial sodium channel α β γ δ
Proton-gated	Amiloride-sensitive cation channel 1 2 3 4
Voltage-gated	Na_vα 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 7A Na_vβ 1 2 3 4

K⁺: Potassium channel

Calcium-activated	BK channel α1 β1 β2 β3 β4 SK channel SK1 SK2 SK3 IK channel IK1 K_Ca 1.1 2.1 2.2 2.3 3.1 4.1 4.2 5.1
Inward-rectifier	K_ATP K_ir 1.1 2.1 2.2 2.3 2.4 2.6 GIRK/K_ir 3.1 3.2 3.3 3.4 K_ir 4.1 4.2 5.1 6.1 6.2 7.1
Tandem pore domain	K2P 1 2 3 4 5 6 7 9 10 12 13 15 16 17 18
Voltage-gated	K_vα1-6 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 2.1 2.2 3.1 3.2 3.3 3.4 4.1 4.2 4.3 5.1 6.1 6.2 6.3 6.4 K_vα7-12 7.1 7.2 7.3 7.4 7.5 8.1 8.2 9.1 9.2 9.3 10.1 10.2 11.1/hERG 11.2 11.3 12.1 12.2 12.3 K_vβ 1 2 3 KCNIP 1 2 3 4 minK/ISK minK/ISK-like MiRP 1 2 3 Shaker (gene)

Miscellaneous

Cl⁻: Chloride channel	Calcium-activated chloride channels Anoctamin ANO1 Bestrophin 1 2 Chloride Channel Accessory 1 2 3 4 CFTR CLCN 1 2 3 4 5 6 7 KA KB CLIC 1 2 3 4 5 6 L1 CLNS 1A 1B
H⁺: Proton channel	HVCN1
M⁺: CNG cation channel	α 1 2 3 4 β 1 2 3 HCN FC 1 2 3 4
M⁺: TRP cation channel	TRPA (1) TRPC 1 2 3 4 4AP 5 6 7 TRPM 1 2 3 4 5 6 7 8 TRPML 1 2 3 TRPN TRPP 1 2 TRPV 1 2 3 4 5 6
H₂O (+ solutes): Porin	Aquaporin 0 1 2 3 4 5 6 7 8 9 Voltage-dependent anion channel 1 2 3 General bacterial porin family
Cytoplasm: Gap junction	Connexin A GJA1 GJA3 GJA4 GJA5 GJA8 GJA9 GJA10 B GJB1 GJB2 GJB3 GJB4 GJB5 GJB6 GJB7 C GJC1 GJC2 GJC3 D GJD2 GJD3 GJD4 Innexin