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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/05/09 18:34:42」(JST)

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Ryanodine receptor 2 (RYR2) is 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, stress-induced polymorphic ventricular tachycardia, and arrhythmogenic right ventricular dysplasia.^[8]

Mice with genetically reduced RYR2 exhibit a lower basal heart rate and fatal arrythmias.^[9]

Interactions

Ryanodine receptor 2 has been shown to interact with:

AKAP6,^[10]^[11]
PRKACA,^[10]
PRKACB,^[10]
PRKACG,^[10] and
SRI.^[12]

References

^ Otsu K, Willard HF, Khanna VK, Zorzato F, Green NM, MacLennan DH (September 1990). "Molecular cloning of cDNA encoding the Ca2+ release channel (ryanodine receptor) of rabbit cardiac muscle sarcoplasmic reticulum". J Biol Chem 265 (23): 13472–83. PMID 2380170.
^ Otsu K, Fujii J, Periasamy M, Difilippantonio M, Uppender M, Ward DC et al. (October 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)". Hum Mol Genet 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". Circ. Res. 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. (15 May 2013). "Cardiomyocyte ATP production, metabolic flexibility, and survival require calcium flux through cardiac ryanodine receptors in vivo". Journal of Biological Chemistry 288 (26): 18975–86. doi:10.1074/jbc.M112.427062. PMID 23678000.
^ Belevych AE, Radwański PB, Carnes CA, Györke S (2013). "'Ryanopathy': causes and manifestations of RyR2 dysfunction in heart failure". Cardiovasc. Res. 98 (2): 240–7. doi:10.1093/cvr/cvt024. PMC 3633158. PMID 23408344.
^ "Entrez Gene: RYR2 ryanodine receptor 2 (cardiac)".
^ Bround MJ, Asghari P, Wambolt RB, Bohunek L, Smits C, Philit M et al. (September 2012). "Cardiac ryanodine receptors control heart rate and rhythmicity in adult mice". Cardiovasc. Res. 96 (3): 372–80. doi:10.1093/cvr/cvs260. 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): 365–76. doi:10.1016/S0092-8674(00)80847-8. PMID 10830164.
^ 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". J. Cell Biol. 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". J. Biol. Chem. 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 US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

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1. 明らかな器質的心疾患のない患者における突然の心停止 sudden cardiac arrest in the absence of apparent structural heart disease
2. カテコラミン誘発多形性心室頻拍および他のQT間隔正常の多形性心室頻拍 catecholaminergic polymorphic ventricular tachycardia and other polymorphic ventricular tachycardias with a normal qt interval
3. 心房細動の機序 mechanisms of atrial fibrillation
4. 不整脈治療におけるカルシウムチャネル遮断剤拮抗剤 calcium channel blockers in the treatment of cardiac arrhythmias
5. 不整脈原性右室心筋症の遺伝学および病因 genetics and pathogenesis of arrhythmogenic right ventricular cardiomyopathy

English Journal

Essential Role of Calmodulin in RyR Inhibition by Dantrolene.

Oo YW1, Gomez-Hurtado N1, Walweel K1, van Helden DF1, Imtiaz MS1, Knollmann BC1, Laver DR2.
Molecular pharmacology.Mol Pharmacol.2015 Jul;88(1):57-63. doi: 10.1124/mol.115.097691. Epub 2015 Apr 28.
Dantrolene is the first line therapy of malignant hyperthermia. Animal studies suggest that dantrolene also protects against heart failure and arrhythmias caused by spontaneous Ca(2+) release. Although dantrolene inhibits Ca(2+) release from the sarcoplasmic reticulum of skeletal and cardiac muscle
PMID 25920678
PMID 25736969

The ryanodine receptor provides high throughput Ca2+-release but is precisely regulated by networks of associated proteins: a focus on proteins relevant to phosphorylation.

O'Brien F1, Venturi E1, Sitsapesan R1.
Biochemical Society transactions.Biochem Soc Trans.2015 Jun 1;43(3):426-33. doi: 10.1042/BST20140297.
Once opened, ryanodine receptors (RyR) are efficient pathways for the release of Ca2+ from the endoplasmic/sarcoplasmic reticulum (ER/SR). The precise nature of the Ca2+-release event, however, requires fine-tuning for the specific process and type of cell involved. For example, the spatial organiz
PMID 26009186

Japanese Journal

心不全･致死的不整脈における細胞内カルシウム放出異常

矢野雅文
山口医学 63(1), 11-16, 2014-02-01
… し病態の悪化に深く関与することを示した.一方,このようなRyR機能異常を正常化することにより心不全の発現を抑制できる可能性が実験的に示されるようになり,RyRは新たな心不全･致死的不整脈の治療ターゲットとしても期待しうる.Two domains within the ryanodine receptor(RyR2)of sarcoplasmic reticulum(SR){N-terminal(0-600)and central(2000-2500)domains:N-C domains},harboring many mutations in CPVT, was found to interact with each other as a regulatory switch for channel …
NAID 120005435141

Increased Phosphorylation of Ca²⁺ Handling Proteins as a Proarrhythmic Mechanism in Myocarditis

Park Hyelim,Park Hyewon,Lee Dajeong [他],Oh Sujung,Lim Jisoo,Hwang Hye jin,Park Sungha,Pak Hui-Nam,Lee Moon-Hyoung,Joung Boyoung
Circulation Journal 78(9), 2292-2301, 2014
… CaMKII autophosphorylation at Thr287 (201%), and RyR2 phosphorylation at Ser2808 (protein kinase A/CaMKII site, 126%) and Ser2814 (CaMKII site, 21%) were increased in rats with myocarditis and reversed by steroid.Conclusions:The myocarditis group had an increased incidence of arrhythmia caused by increased phosphorylation of Ca2+handling proteins. …
NAID 130004677617

心不全・致死的不整脈における細胞内カルシウム放出異常

矢野雅文
山口医学 63(1), 11-16, 2014
心筋細胞膜の脱分極が生じるごとにL型 Ca2+チャネル（LTCC）から少量のCa2+が流入し，その流入Ca2+がトリガーとなり筋小胞体（SR）膜上にあるCa2+放出チャネルのリアノジン受容体（RyR）からの大量のCa2+放出を引き起こす．細胞内の増加したCa2+は，収縮蛋白を活性化した後，SRのCa2+-ATPaseによりSR内に再び取り込まれるとともに，一部はNa+/Ca2+交換機構や細胞膜Ca …
NAID 130004476032

Related Pictures

RyR2 Ca2+ leak, mechanisms of RyR2 RyR2 The leaky RyR2 hypothesis: phosphorylation RyR2 and Calcium RYR2 mutations, bradycardia, and follow up Ryanodine Receptor 2 (RYR2) (pSer2814) pAb Calcium signalling: dynamics, homeostasis Ryanodine Receptor 2 (RyR2) | InTechOpen

★リンクテーブル★

リンク元	「リアノジン受容体2型」「RyR1」「RyR3」「cardiac ryanodine receptor」「ryanodine receptor calcium release channel」
関連記事	「RyR」

「リアノジン受容体2型」

Ryanodine receptor 2 (cardiac)
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	4JKQ
Identifiers
Symbols	RYR2 ; ARVC2; ARVD2; RYR-2; RyR; VTSIP
External IDs	OMIM: 180902 MGI: 99685 HomoloGene: 37423 IUPHAR: 748 ChEMBL: 4403 GeneCards: RYR2 Gene
Gene ontology
Molecular function	• intracellular ligand-gated calcium channel activity; • ryanodine-sensitive calcium-release channel activity; • calcium channel activity; • calcium ion binding; • protein binding; • calmodulin binding; • calcium-release channel activity; • enzyme binding; • protein kinase A catalytic subunit binding; • protein kinase A regulatory subunit binding; • identical protein binding; • protein self-association; • suramin binding; • ion channel binding; • calcium-induced calcium release activity;
Cellular component	• plasma membrane; • junctional sarcoplasmic reticulum membrane; • membrane; • sarcoplasmic reticulum; • Z disc; • sarcoplasmic reticulum membrane; • calcium channel complex; • protein complex; • extracellular vesicular exosome;
Biological process	• response to hypoxia; • regulation of heart rate; • embryonic heart tube morphogenesis; • left ventricular cardiac muscle tissue morphogenesis; • cardiac muscle hypertrophy; • detection of calcium ion; • calcium ion transport; • cellular calcium ion homeostasis; • positive regulation of heart rate; • regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion; • release of sequestered calcium ion into cytosol by sarcoplasmic reticulum; • calcium-mediated signaling; • BMP signaling pathway; • response to caffeine; • ion transmembrane transport; • calcium-mediated signaling using intracellular calcium source; • release of sequestered calcium ion into cytosol; • positive regulation of sequestering of calcium ion; • cytosolic calcium ion homeostasis; • response to redox state; • transmembrane transport; • regulation of cardiac muscle contraction; • cardiac muscle contraction; • canonical Wnt signaling pathway; • calcium ion transport into cytosol; • sarcoplasmic reticulum calcium ion transport; • calcium ion transmembrane transport; • cellular response to caffeine; • cellular response to epinephrine stimulus; • establishment of protein localization to endoplasmic reticulum; • ventricular cardiac muscle cell action potential; • Purkinje myocyte to ventricular cardiac muscle cell signaling; • cell communication by electrical coupling involved in cardiac conduction; • positive regulation of ryanodine-sensitive calcium-release channel activity by adrenergic receptor signaling pathway involved in positive regulation of cardiac muscle contraction; • type B pancreatic cell apoptotic process; • positive regulation of calcium-transporting ATPase activity;
	Sources: Amigo / QuickGO
Orthologs
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