Search TCDB: (?)
TCDB is operated by the Saier Lab Bioinformatics Group
« See all members of the family


1.A.3.1.1
Ryanodine receptor Ca2+ release channel, RyR2.  Causes Ca2+ release from the E.R. and consequent cardiac arrhythmia (Chelu and Wehrens, 2007). Associates with FKBP12.6, but phosphorylation by protein kinase A on serine-2030 causes dissociation (Jones et al., 2008). An interaction site for FKBP12.6 may be present at the RyR2 C terminus, proximal to the channel pore, a sterically appropriate location that would enable this protein to play a role in the modulation of this channel (Zissimopoulos and Lai 2005). Enhanced binding of calmodulin corrects arrhythmogenic channel disorder in myocytes (Fukuda et al. 2014).  RyR2s can open spontaneously, giving rise to spatially-confined Ca2+ release events known as "sparks." They are organized in a lattice to form clusters in the junctional sarcoplasmic reticulum membrane. The spatial arrangement of RyR2s within clusters strongly influences the frequency of Ca2+ sparks (Walker et al. 2015).  Structures of RyR2 from porcine heart in both the open and closed states at near atomic resolutions have been determined using single-particle electron cryomicroscopy (Peng et al. 2016). Structural comparisons revealed breathing motions of the overall cytoplasmic region resulting from the interdomain movements of amino-terminal domains (NTDs), Helical domains, and Handle domains, whereas little intradomain shifts are observed in these armadillo repeat-containing domains. Outward rotations of the central domains, which integrate the conformational changes of the cytoplasmic region, lead to the dilation of the cytoplasmic gate through coupled motions. These observations provide insight into the gating mechanism of RyRs (Peng et al. 2016). RyR2 is subject ot regulation by cytoplasmic Zn2+ (>1nM), and this regulation plays a key role in diastolic SR Ca2+ leakage in cardiac muscle (Reilly-O'Donnell et al. 2017). Ryanodine receptor-mediated SR Ca2+ efflux is apparently balanced by concomitant counterion currents across the SR membrane (Sanchez et al. 2018). Electrical polarity-dependent gating and a unique subconductance of RyR2 is induced by S-adenosyl methionine via the ATP binding site. Thus, SAM may alter the conformation of the RyR2 ion conduction pathway (Kampfer and Balog 2021). The brief opening mode of the mitochondrial permeability transition pore (mPTP) serves as a calcium (Ca2+) release valve to prevent mitochondrial Ca2+ (mCa2+) overload. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a stress-induced arrhythmic syndrome due to mutations in the Ca2+ release channel complex of ryanodine receptor 2 (RyR2). Genetic inhibition of mPTP exacerbates RyR2 dysfunction in CPVT by increasing activation of the CaMKII pathway and subsequent hyperphosphorylation of RyR2 (Deb et al. 2023). Protamine reversibly modulates the calcium release channel/ryanodine receptor 2 (RyR2) and voltage-dependent cardiac RyR2 (Yamada et al. 2023). Calcium release deficiency syndrome (CRDS) is a form of inherited arrhythmia caused by damaging loss-of-function variants in the cardiac ryanodine receptor (RyR2) (Kallas et al. 2023). Cardiomyocyte ryanodine receptor 2 clusters expand and coalesce after application of isoproterenol. Thus, isoproterenol induces rapid, significant, changes in the molecular architecture of excitation-contraction coupling (Scriven et al. 2023).  Distinct patterns and length scales of RyR and IP3R1 co-clustering at contact sites between the ER and the surface plasmalemma that encode the positions and the quantity of Ca2+ released at each Ca2+ spark (Hurley et al. 2023).

Accession Number:Q92736
Protein Name:RYR2
Length:4965
Molecular Weight:564742.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:10
Location1 / Topology2 / Orientation3: Membrane1 / Multi-pass membrane protein2
Substrate calcium(2+)

Cross database links:

Pfam: PF08709    PF00520    PF02815    PF08454    PF06459    PF01365    PF02026    PF00622   
OMIM: 180902  gene
600996  phenotype
604772  phenotype

Gene Ontology

GO:0034704 C:calcium channel complex
GO:0005886 C:plasma membrane
GO:0001950 C:plasma membrane enriched fraction
GO:0033017 C:sarcoplasmic reticulum membrane
GO:0005509 F:calcium ion binding
GO:0005516 F:calmodulin binding
GO:0042802 F:identical protein binding
GO:0034236 F:protein kinase A catalytic subunit binding
GO:0034237 F:protein kinase A regulatory subunit binding
GO:0004872 F:receptor activity
GO:0005219 F:ryanodine-sensitive calcium-release channel...
GO:0043924 F:suramin binding
GO:0060048 P:cardiac muscle contraction
GO:0005513 P:detection of calcium ion
GO:0008627 P:induction of apoptosis by ionic changes
GO:0010881 P:regulation of cardiac muscle contraction by...
GO:0014808 P:release of sequestered calcium ion into cyt...
GO:0031000 P:response to caffeine
GO:0001666 P:response to hypoxia
GO:0051775 P:response to redox state
GO:0055085 P:transmembrane transport

References (15)

[1] “The human cardiac muscle ryanodine receptor-calcium release channel: identification, primary structure and topological analysis.”  Tunwell R.E.A.et.al.   8809036
[2] “Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2).”  Tiso N.et.al.   11159936
[3] “The DNA sequence and biological annotation of human chromosome 1.”  Gregory S.G.et.al.   16710414
[4] “Differential expression of ryanodine receptor RyR2 mRNA in the non-pregnant and pregnant human myometrium.”  Awad S.S.et.al.   9148749
[5] “Partial cloning and differential expression of ryanodine receptor/calcium-release channel genes in human tissues including the hippocampus and cerebellum.”  Martin C.et.al.   9607712
[6] “Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia.”  Priori S.G.et.al.   11208676
[7] “Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia.”  Laitinen P.J.et.al.   11157710
[8] “Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia.”  Priori S.G.et.al.   12093772
[9] “Screening for ryanodine receptor type 2 mutations in families with effort-induced polymorphic ventricular arrhythmias and sudden death: early diagnosis of asymptomatic carriers.”  Bauce B.et.al.   12106942
[10] “Molecular genetics of exercise-induced polymorphic ventricular tachycardia: identification of three novel cardiac ryanodine receptor mutations and two common calsequestrin 2 amino-acid polymorphisms.”  Laitinen P.J.et.al.   14571276
[11] “Spectrum and frequency of cardiac channel defects in swimming-triggered arrhythmia syndromes.”  Choi G.et.al.   15466642
[12] “Gene symbol: RYR2. Disease: effort-induced polymorphic ventricular arrhythmias.”  Bagattin A.et.al.   15046072
[13] “Gene symbol: RYR2. Disease: effort-induced polymorphic ventricular arrhythmias.”  Bagattin A.et.al.   15046073
[14] “Targeted mutational analysis of the RyR2-encoded cardiac ryanodine receptor in sudden unexplained death: a molecular autopsy of 49 medical examiner/coroner's cases.”  Tester D.J.et.al.   15544015
[15] “Loss of luminal Ca(2+) activation in the cardiac ryanodine receptor is associated with ventricular fibrillation and sudden death.”  Jiang D.et.al.   17984046
Structure:
4JKQ   6Y4O   6Y4P     

External Searches:

Analyze:

Predict TMSs (Predict number of transmembrane segments)
Window Size: Angle:  
FASTA formatted sequence 
1:	MGARAKTRSS SCELMMKWFC SAPQPSTKNN RSYAWQQKDL ATDFVSWSPL PIPRMCPQTS 
61:	PSAPLCWSSP SLSGRCRRCW LTPWRNQKGQ VDVEKWKFMM KTAQGGGHRT LLYGHAILLR 
121:	HSYSGMYLCC LSTSRSSTDK LAFDVGLQED TTGEACWWTI HPASKQRSEG EKVRVGDDLI 
181:	LVSVSSERYL HLSYGNGSLH VDAAFQQTLW SVAPISSGSE AAQGYLIGGD VLRLLHGHMD 
241:	ECLTVPSGEH GEEQRRTVHY EGGAVSVHAR SLWRLETLRV AWSGSHIRWG QPFRLRHVTT 
301:	GKYLSLMEDK NLLLMDKEKA DVKSTAFTFR SSKEKLDVGV RKEVDGMGTS EIKYGDSVCY 
361:	IQHVDTGLWL TYQSVDVKSV RMGSIQRKAI MHHEGHMDDG ISLSRSQHEE SRTARVIRST 
421:	VFLFNRFIRG LDALSKKAKA STVDLPIESV SLSLQDLIGY FHPPDEHLEH EDKQNRLRAL 
481:	KNRQNLFQEE GMINLVLECI DRLHVYSSAA HFADVAGREA GESWKSILNS LYELLAALIR 
541:	GNRKNCAQFS GSLDWLISRL ERLEASSGIL EVLHCVLVES PEALNIIKEG HIKSIISLLD 
601:	KHGRNHKVLD VLCSLCVCHG VAVRSNQHLI CDNLLPGRDL LLQTRLVNHV SSMRPNIFLG 
661:	VSEGSAQYKK WYYELMVDHT EPFVTAEATH LRVGWASTEG YSPYPGGGEE WGGNGVGDDL 
721:	FSYGFDGLHL WSGCIARTVS SPNQHLLRTD DVISCCLDLS APSISFRING QPVQGMFENF 
781:	NIDGLFFPVV SFSAGIKVRF LLGGRHGEFK FLPPPGYAPC YEAVLPKEKL KVEHSREYKQ 
841:	ERTYTRDLLG PTVSLTQAAF TPIPVDTSQI VLPPHLERIR EKLAENIHEL WVMNKIELGW 
901:	QYGPVRDDNK RQHPCLVEFS KLPEQERNYN LQMSLETLKT LLALGCHVGI SDEHAEDKVK 
961:	KMKLPKNYQL TSGYKPAPMD LSFIKLTPSQ EAMVDKLAEN AHNVWARDRI RQGWTYGIQQ 
1021:	DVKNRRNPRL VPYTLLDDRT KKSNKDSLRE AVRTLLGYGY NLEAPDQDHA ARAEVCSGTG 
1081:	ERFRIFRAEK TYAVKAGRWY FEFETVTAGD MRVGWSRPGC QPDQELGSDE RAFAFDGFKA 
1141:	QRWHQGNEHY GRSWQAGDVV GCMVDMNEHT MMFTLNGEIL LDDSGSELAF KDFDVGDGFI 
1201:	PVCSLGVAQV GRMNFGKDVS TLKYFTICGL QEGYEPFAVN TNRDITMWLS KRLPQFLQVP 
1261:	SNHEHIEVTR IDGTIDSSPC LKVTQKSFGS QNSNTDIMFY RLSMPIECAE VFSKTVAGGL 
1321:	PGAGLFGPKN DLEDYDADSD FEVLMKTAHG HLVPDRVDKD KEATKPEFNN HKDYAQEKPS 
1381:	RLKQRFLLRR TKPDYSTSHS ARLTEDVLAD DRDDYDFLMQ TSTYYYSVRI FPGQEPANVW 
1441:	VGWITSDFHQ YDTGFDLDRV RTVTVTLGDE KGKVHESIKR SNCYMVCAGE SMSPGQGRNN 
1501:	NGLEIGCVVD AASGLLTFIA NGKELSTYYQ VEPSTKLFPA VFAQATSPNV FQFELGRIKN 
1561:	VMPLSAGLFK SEHKNPVPQC PPRLHVQFLS HVLWSRMPNQ FLKVDVSRIS ERQGWLVQCL 
1621:	DPLQFMSLHI PEENRSVDIL ELTEQEELLK FHYHTLRLYS AVCALGNHRV AHALCSHVDE 
1681:	PQLLYAIENK YMPGLLRAGY YDLLIDIHLS SYATARLMMN NEYIVPMTEE TKSITLFPDE 
1741:	NKKHGLPGIG LSTSLRPRMQ FSSPSFVSIS NECYQYSPEF PLDILKSKTI QMLTEAVKEG 
1801:	SLHARDPVGG TTEFLFVPLI KLFYTLLIMG IFHNEDLKHI LQLIEPSVFK EAATPEEESD 
1861:	TLEKELSVDD AKLQGAGEEE AKGGKRPKEG LLQMKLPEPV KLQMCLLLQY LCDCQVRHRI 
1921:	EAIVAFSDDF VAKLQDNQRF RYNEVMQALN MSAALTARKT KEFRSPPQEQ INMLLNFKDD 
1981:	KSECPCPEEI RDQLLDFHED LMTHCGIELD EDGSLDGNSD LTIRGRLLSL VEKVTYLKKK 
2041:	QAEKPVESDS KKSSTLQQLI SETMVRWAQE SVIEDPELVR AMFVLLHRQY DGIGGLVRAL 
2101:	PKTYTINGVS VEDTINLLAS LGQIRSLLSV RMGKEEEKLM IRGLGDIMNN KVFYQHPNLM 
2161:	RALGMHETVM EVMVNVLGGG ESKEITFPKM VANCCRFLCY FCRISRQNQK AMFDHLSYLL 
2221:	ENSSVGLASP AMRGSTPLDV AAASVMDNNE LALALREPDL EKVVRYLAGC GLQSCQMLVS 
2281:	KGYPDIGWNP VEGERYLDFL RFAVFCNGES VEENANVVVR LLIRRPECFG PALRGEGGNG 
2341:	LLAAMEEAIK IAEDPSRDGP SPNSGSSKTL DTEEEEDDTI HMGNAIMTFY SALIDLLGRC 
2401:	APEMHLIHAG KGEAIRIRSI LRSLIPLGDL VGVISIAFQM PTIAKDGNVV EPDMSAGFCP 
2461:	DHKAAMVLFL DRVYGIEVQD FLLHLLEVGF LPDLRAAASL DTAALSATDM ALALNRYLCT 
2521:	AVLPLLTRCA PLFAGTEHHA SLIDSLLHTV YRLSKGCSLT KAQRDSIEVC LLSICGQLRP 
2581:	SMMQHLLRRL VFDVPLLNEH AKMPLKLLTN HYERCWKYYC LPGGWGNFGA ASEEELHLSR 
2641:	KLFWGIFDAL SQKKYEQELF KLALPCLSAV AGALPPDYME SNYVSMMEKQ SSMDSEGNFN 
2701:	PQPVDTSNIT IPEKLEYFIN KYAEHSHDKW SMDKLANGWI YGEIYSDSSK VQPLMKPYKL 
2761:	LSEKEKEIYR WPIKESLKTM LAWGWRIERT REGDSMALYN RTRRISQTSQ VSVDAAHGYS 
2821:	PRAIDMSNVT LSRDLHAMAE MMAENYHNIW AKKKKMELES KGGGNHPLLV PYDTLTAKEK 
2881:	AKDREKAQDI LKFLQINGYA VSRGFKDLEL DTPSIEKRFA YSFLQQLIRY VDEAHQYILE 
2941:	FDGGSRGKGE HFPYEQEIKF FAKVVLPLID QYFKNHRLYF LSAASRPLCS GGHASNKEKE 
3001:	MVTSLFCKLG VLVRHRISLF GNDATSIVNC LHILGQTLDA RTVMKTGLES VKSALRAFLD 
3061:	NAAEDLEKTM ENLKQGQFTH TRNQPKGVTQ IINYTTVALL PMLSSLFEHI GQHQFGEDLI 
3121:	LEDVQVSCYR ILTSLYALGT SKSIYVERQR SALGECLAAF AGAFPVAFLE THLDKHNIYS 
3181:	IYNTKSSRER AALSLPTNVE DVCPNIPSLE KLMEEIVELA ESGIRYTQMP HVMEVILPML 
3241:	CSYMSRWWEH GPENNPERAE MCCTALNSEH MNTLLGNILK IIYNNLGIDE GAWMKRLAVF 
3301:	SQPIINKVKP QLLKTHFLPL MEKLKKKAAT VVSEEDHLKA EARGDMSEAE LLILDEFTTL 
3361:	ARDLYAFYPL LIRFVDYNRA KWLKEPNPEA EELFRMVAEV FIYWSKSHNF KREEQNFVVQ 
3421:	NEINNMSFLI TDTKSKMSKA AVSDQERKKM KRKGDRYSMQ TSLIVAALKR LLPIGLNICA 
3481:	PGDQELIALA KNRFSLKDTE DEVRDIIRSN IHLQGKLEDP AIRWQMALYK DLPNRTDDTS 
3541:	DPEKTVERVL DIANVLFHLE QKSKRVGRRH YCLVEHPQRS KKAVWHKLLS KQRKRAVVAC 
3601:	FRMAPLYNLP RHRAVNLFLQ GYEKSWIETE EHYFEDKLIE DLAKPGAEPP EEDEGTKRVD 
3661:	PLHQLILLFS RTALTEKCKL EEDFLYMAYA DIMAKSCHDE EDDDGEEEVK SFEEKEMEKQ 
3721:	KLLYQQARLH DRGAAEMVLQ TISASKGETG PMVAATLKLG IAILNGGNST VQQKMLDYLK 
3781:	EKKDVGFFQS LAGLMQSCSV LDLNAFERQN KAEGLGMVTE EGSGEKVLQD DEFTCDLFRF 
3841:	LQLLCEGHNS DFQNYLRTQT GNNTTVNIII STVDYLLRVQ ESISDFYWYY SGKDVIDEQG 
3901:	QRNFSKAIQV AKQVFNTLTE YIQGPCTGNQ QSLAHSRLWD AVVGFLHVFA HMQMKLSQDS 
3961:	SQIELLKELM DLQKDMVVML LSMLEGNVVN GTIGKQMVDM LVESSNNVEM ILKFFDMFLK 
4021:	LKDLTSSDTF KEYDPDGKGV ISKRDFHKAM ESHKHYTQSE TEFLLSCAET DENETLDYEE 
4081:	FVKRFHEPAK DIGFNVAVLL TNLSEHMPND TRLQTFLELA ESVLNYFQPF LGRIEIMGSA 
4141:	KRIERVYFEI SESSRTQWEK PQVKESKRQF IFDVVNEGGE KEKMELFVNF CEDTIFEMQL 
4201:	AAQISESDLN ERSANKEESE KERPEEQGPR MAFFSILTVR SALFALRYNI LTLMRMLSLK 
4261:	SLKKQMKKVK KMTVKDMVTA FFSSYWSIFM TLLHFVASVF RGFFRIICSL LLGGSLVEGA 
4321:	KKIKVAELLA NMPDPTQDEV RGDGEEGERK PLEAALPSED LTDLKELTEE SDLLSDIFGL 
4381:	DLKREGGQYK LIPHNPNAGL SDLMSNPVPM PEVQEKFQEQ KAKEEEKEEK EETKSEPEKA 
4441:	EGEDGEKEEK AKEDKGKQKL RQLHTHRYGE PEVPESAFWK KIIAYQQKLL NYFARNFYNM 
4501:	RMLALFVAFA INFILLFYKV STSSVVEGKE LPTRSSSENA KVTSLDSSSH RIIAVHYVLE 
4561:	ESSGYMEPTL RILAILHTVI SFFCIIGYYC LKVPLVIFKR EKEVARKLEF DGLYITEQPS 
4621:	EDDIKGQWDR LVINTQSFPN NYWDKFVKRK VMDKYGEFYG RDRISELLGM DKAALDFSDA 
4681:	REKKKPKKDS SLSAVLNSID VKYQMWKLGV VFTDNSFLYL AWYMTMSVLG HYNNFFFAAH 
4741:	LLDIAMGFKT LRTILSSVTH NGKQLVLTVG LLAVVVYLYT VVAFNFFRKF YNKSEDGDTP 
4801:	DMKCDDMLTC YMFHMYVGVR AGGGIGDEIE DPAGDEYEIY RIIFDITFFF FVIVILLAII 
4861:	QGLIIDAFGE LRDQQEQVKE DMETKCFICG IGNDYFDTVP HGFETHTLQE HNLANYLFFL 
4921:	MYLINKDETE HTGQESYVWK MYQERCWEFF PAGDCFRKQY EDQLN