Rijanodinski receptor 2 (RYR2) je protein koji je prvenstveno nađen u miokardnim mišićima. Kod ljudi kodiran je genom RYR2.[5][6][7] U procesu srčanog oslobađanja kalcija inducirano kalcijem, RYR2 je glavni posrednik za sarkoplazmatsko oslobađanje uskladištenih iona kalcija.

RYR2
Dostupne strukture
PDBPretraga ortologa: PDBe RCSB
Spisak PDB ID kodova

4JKQ

Identifikatori
AliasiRYR2
Vanjski ID-jeviOMIM: 180902 MGI: 99685 HomoloGene: 37423 GeneCards: RYR2
Lokacija gena (čovjek)
Hromosom 1 (čovjek)
Hrom.Hromosom 1 (čovjek)[1]
Hromosom 1 (čovjek)
Genomska lokacija za RYR2
Genomska lokacija za RYR2
Bend1q43Početak237,042,184 bp[1]
Kraj237,833,988 bp[1]
Lokacija gena (miš)
Hromosom 13 (miš)
Hrom.Hromosom 13 (miš)[2]
Hromosom 13 (miš)
Genomska lokacija za RYR2
Genomska lokacija za RYR2
Bend13 A1|13 4.38 cMPočetak11,553,102 bp[2]
Kraj12,106,945 bp[2]
Ontologija gena
Molekularna funkcija 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
GO:0001948, GO:0016582 vezivanje za proteine
vezivanje identičnih proteina
vezivanje enzima
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
Ćelijska komponenta integral component of membrane
Kalcijski kanal
membrana
Sarkomera
junctional sarcoplasmic reticulum membrane
Sarkoplazmatski retikulum
Z discdkac
sarcoplasmic reticulum membrane
smooth endoplasmic reticulum
ćelijska membrana
GO:0009327 makromolekulani kompleks
cytoplasmic vesicle membrane
Sarkolema
Biološki proces 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
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez
Ensembl
UniProt
RefSeq (mRNK)

NM_001035

NM_023868

RefSeq (bjelančevina)

NP_001026

NP_076357

Lokacija (UCSC)Chr 1: 237.04 – 237.83 MbChr 13: 11.55 – 12.11 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš

Struktura

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Kanal se sastoji od RYR2 homotetramera i  FK506-vezujućih proteina koji su u stehiometrijskom omjeru 1: 4. Na funkciju kalcijevih kanala utiče specifični tip izomera FK506 koji djeluje u interakciji s proteinom RYR2, zbog razlika u vezanju i drugih faktora.[8]

Aminokiselinska sekvenca
1020304050
MADGGEGEDEIQFLRTDDEVVLQCTATIHKEQQKLCLAAEGFGNRLCFLE
STSNSKNVPPDLSICTFVLEQSLSVRALQEMLANTVEKSEGQVDVEKWKF
MMKTAQGGGHRTLLYGHAILLRHSYSGMYLCCLSTSRSSTDKLAFDVGLQ
EDTTGEACWWTIHPASKQRSEGEKVRVGDDLILVSVSSERYLHLSYGNGS
LHVDAAFQQTLWSVAPISSGSEAAQGYLIGGDVLRLLHGHMDECLTVPSG
EHGEEQRRTVHYEGGAVSVHARSLWRLETLRVAWSGSHIRWGQPFRLRHV
TTGKYLSLMEDKNLLLMDKEKADVKSTAFTFRSSKEKLDVGVRKEVDGMG
TSEIKYGDSVCYIQHVDTGLWLTYQSVDVKSVRMGSIQRKAIMHHEGHMD
DGISLSRSQHEESRTARVIRSTVFLFNRFIRGLDALSKKAKASTVDLPIE
SVSLSLQDLIGYFHPPDEHLEHEDKQNRLRALKNRQNLFQEEGMINLVLE
CIDRLHVYSSAAHFADVAGREAGESWKSILNSLYELLAALIRGNRKNCAQ
FSGSLDWLISRLERLEASSGILEVLHCVLVESPEALNIIKEGHIKSIISL
LDKHGRNHKVLDVLCSLCVCHGVAVRSNQHLICDNLLPGRDLLLQTRLVN
HVSSMRPNIFLGVSEGSAQYKKWYYELMVDHTEPFVTAEATHLRVGWAST
EGYSPYPGGGEEWGGNGVGDDLFSYGFDGLHLWSGCIARTVSSPNQHLLR
TDDVISCCLDLSAPSISFRINGQPVQGMFENFNIDGLFFPVVSFSAGIKV
RFLLGGRHGEFKFLPPPGYAPCYEAVLPKEKLKVEHSREYKQERTYTRDL
LGPTVSLTQAAFTPIPVDTSQIVLPPHLERIREKLAENIHELWVMNKIEL
GWQYGPVRDDNKRQHPCLVEFSKLPEQERNYNLQMSLETLKTLLALGCHV
GISDEHAEDKVKKMKLPKNYQLTSGYKPAPMDLSFIKLTPSQEAMVDKLA
ENAHNVWARDRIRQGWTYGIQQDVKNRRNPRLVPYTLLDDRTKKSNKDSL
REAVRTLLGYGYNLEAPDQDHAARAEVCSGTGERFRIFRAEKTYAVKAGR
WYFEFETVTAGDMRVGWSRPGCQPDQELGSDERAFAFDGFKAQRWHQGNE
HYGRSWQAGDVVGCMVDMNEHTMMFTLNGEILLDDSGSELAFKDFDVGDG
FIPVCSLGVAQVGRMNFGKDVSTLKYFTICGLQEGYEPFAVNTNRDITMW
LSKRLPQFLQVPSNHEHIEVTRIDGTIDSSPCLKVTQKSFGSQNSNTDIM
FYRLSMPIECAEVFSKTVAGGLPGAGLFGPKNDLEDYDADSDFEVLMKTA
HGHLVPDRVDKDKEATKPEFNNHKDYAQEKPSRLKQRFLLRRTKPDYSTS
HSARLTEDVLADDRDDYDFLMQTSTYYYSVRIFPGQEPANVWVGWITSDF
HQYDTGFDLDRVRTVTVTLGDEKGKVHESIKRSNCYMVCAGESMSPGQGR
NNNGLEIGCVVDAASGLLTFIANGKELSTYYQVEPSTKLFPAVFAQATSP
NVFQFELGRIKNVMPLSAGLFKSEHKNPVPQCPPRLHVQFLSHVLWSRMP
NQFLKVDVSRISERQGWLVQCLDPLQFMSLHIPEENRSVDILELTEQEEL
LKFHYHTLRLYSAVCALGNHRVAHALCSHVDEPQLLYAIENKYMPGLLRA
GYYDLLIDIHLSSYATARLMMNNEYIVPMTEETKSITLFPDENKKHGLPG
IGLSTSLRPRMQFSSPSFVSISNECYQYSPEFPLDILKSKTIQMLTEAVK
EGSLHARDPVGGTTEFLFVPLIKLFYTLLIMGIFHNEDLKHILQLIEPSV
FKEAATPEEESDTLEKELSVDDAKLQGAGEEEAKGGKRPKEGLLQMKLPE
PVKLQMCLLLQYLCDCQVRHRIEAIVAFSDDFVAKLQDNQRFRYNEVMQA
LNMSAALTARKTKEFRSPPQEQINMLLNFKDDKSECPCPEEIRDQLLDFH
EDLMTHCGIELDEDGSLDGNSDLTIRGRLLSLVEKVTYLKKKQAEKPVES
DSKKSSTLQQLISETMVRWAQESVIEDPELVRAMFVLLHRQYDGIGGLVR
ALPKTYTINGVSVEDTINLLASLGQIRSLLSVRMGKEEEKLMIRGLGDIM
NNKVFYQHPNLMRALGMHETVMEVMVNVLGGGESKEITFPKMVANCCRFL
CYFCRISRQNQKAMFDHLSYLLENSSVGLASPAMRGSTPLDVAAASVMDN
NELALALREPDLEKVVRYLAGCGLQSCQMLVSKGYPDIGWNPVEGERYLD
FLRFAVFCNGESVEENANVVVRLLIRRPECFGPALRGEGGNGLLAAMEEA
IKIAEDPSRDGPSPNSGSSKTLDTEEEEDDTIHMGNAIMTFYSALIDLLG
RCAPEMHLIHAGKGEAIRIRSILRSLIPLGDLVGVISIAFQMPTIAKDGN
VVEPDMSAGFCPDHKAAMVLFLDRVYGIEVQDFLLHLLEVGFLPDLRAAA
SLDTAALSATDMALALNRYLCTAVLPLLTRCAPLFAGTEHHASLIDSLLH
TVYRLSKGCSLTKAQRDSIEVCLLSICGQLRPSMMQHLLRRLVFDVPLLN
EHAKMPLKLLTNHYERCWKYYCLPGGWGNFGAASEEELHLSRKLFWGIFD
ALSQKKYEQELFKLALPCLSAVAGALPPDYMESNYVSMMEKQSSMDSEGN
FNPQPVDTSNITIPEKLEYFINKYAEHSHDKWSMDKLANGWIYGEIYSDS
SKVQPLMKPYKLLSEKEKEIYRWPIKESLKTMLAWGWRIERTREGDSMAL
YNRTRRISQTSQVSVDAAHGYSPRAIDMSNVTLSRDLHAMAEMMAENYHN
IWAKKKKMELESKGGGNHPLLVPYDTLTAKEKAKDREKAQDILKFLQING
YAVSRGFKDLELDTPSIEKRFAYSFLQQLIRYVDEAHQYILEFDGGSRGK
GEHFPYEQEIKFFAKVVLPLIDQYFKNHRLYFLSAASRPLCSGGHASNKE
KEMVTSLFCKLGVLVRHRISLFGNDATSIVNCLHILGQTLDARTVMKTGL
ESVKSALRAFLDNAAEDLEKTMENLKQGQFTHTRNQPKGVTQIINYTTVA
LLPMLSSLFEHIGQHQFGEDLILEDVQVSCYRILTSLYALGTSKSIYVER
QRSALGECLAAFAGAFPVAFLETHLDKHNIYSIYNTKSSRERAALSLPTN
VEDVCPNIPSLEKLMEEIVELAESGIRYTQMPHVMEVILPMLCSYMSRWW
EHGPENNPERAEMCCTALNSEHMNTLLGNILKIIYNNLGIDEGAWMKRLA
VFSQPIINKVKPQLLKTHFLPLMEKLKKKAATVVSEEDHLKAEARGDMSE
AELLILDEFTTLARDLYAFYPLLIRFVDYNRAKWLKEPNPEAEELFRMVA
EVFIYWSKSHNFKREEQNFVVQNEINNMSFLITDTKSKMSKAAVSDQERK
KMKRKGDRYSMQTSLIVAALKRLLPIGLNICAPGDQELIALAKNRFSLKD
TEDEVRDIIRSNIHLQGKLEDPAIRWQMALYKDLPNRTDDTSDPEKTVER
VLDIANVLFHLEQKSKRVGRRHYCLVEHPQRSKKAVWHKLLSKQRKRAVV
ACFRMAPLYNLPRHRAVNLFLQGYEKSWIETEEHYFEDKLIEDLAKPGAE
PPEEDEGTKRVDPLHQLILLFSRTALTEKCKLEEDFLYMAYADIMAKSCH
DEEDDDGEEEVKSFEEKEMEKQKLLYQQARLHDRGAAEMVLQTISASKGE
TGPMVAATLKLGIAILNGGNSTVQQKMLDYLKEKKDVGFFQSLAGLMQSC
SVLDLNAFERQNKAEGLGMVTEEGSGEKVLQDDEFTCDLFRFLQLLCEGH
NSDFQNYLRTQTGNNTTVNIIISTVDYLLRVQESISDFYWYYSGKDVIDE
QGQRNFSKAIQVAKQVFNTLTEYIQGPCTGNQQSLAHSRLWDAVVGFLHV
FAHMQMKLSQDSSQIELLKELMDLQKDMVVMLLSMLEGNVVNGTIGKQMV
DMLVESSNNVEMILKFFDMFLKLKDLTSSDTFKEYDPDGKGVISKRDFHK
AMESHKHYTQSETEFLLSCAETDENETLDYEEFVKRFHEPAKDIGFNVAV
LLTNLSEHMPNDTRLQTFLELAESVLNYFQPFLGRIEIMGSAKRIERVYF
EISESSRTQWEKPQVKESKRQFIFDVVNEGGEKEKMELFVNFCEDTIFEM
QLAAQISESDLNERSANKEESEKERPEEQGPRMAFFSILTVRSALFALRY
NILTLMRMLSLKSLKKQMKKVKKMTVKDMVTAFFSSYWSIFMTLLHFVAS
VFRGFFRIICSLLLGGSLVEGAKKIKVAELLANMPDPTQDEVRGDGEEGE
RKPLEAALPSEDLTDLKELTEESDLLSDIFGLDLKREGGQYKLIPHNPNA
GLSDLMSNPVPMPEVQEKFQEQKAKEEEKEEKEETKSEPEKAEGEDGEKE
EKAKEDKGKQKLRQLHTHRYGEPEVPESAFWKKIIAYQQKLLNYFARNFY
NMRMLALFVAFAINFILLFYKVSTSSVVEGKELPTRSSSENAKVTSLDSS
SHRIIAVHYVLEESSGYMEPTLRILAILHTVISFFCIIGYYCLKVPLVIF
KREKEVARKLEFDGLYITEQPSEDDIKGQWDRLVINTQSFPNNYWDKFVK
RKVMDKYGEFYGRDRISELLGMDKAALDFSDAREKKKPKKDSSLSAVLNS
IDVKYQMWKLGVVFTDNSFLYLAWYMTMSVLGHYNNFFFAAHLLDIAMGF
KTLRTILSSVTHNGKQLVLTVGLLAVVVYLYTVVAFNFFRKFYNKSEDGD
TPDMKCDDMLTCYMFHMYVGVRAGGGIGDEIEDPAGDEYEIYRIIFDITF
FFFVIVILLAIIQGLIIDAFGELRDQQEQVKEDMETKCFICGIGNDYFDT
VPHGFETHTLQEHNLANYLFFLMYLINKDETEHTGQESYVWKMYQERCWE
FFPAGDCFRKQYEDQLN
Simboli

Funkcija

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Protein RYR2 funkcionira kao glavna komponenta kalcijevog kanala u sarkoplazmatskom retikulumu koji opskrbljuje srčani mišić ionima tokom sistola.  Da bi omogućio kontrakciju srčanog mišića, kalcijev priliv kroz naponski ograničeni  L-tip kalcijskog kanala   u plazemsmembrani omogućava da se ioni kalcija vežu za RYR2, koji se nalazi na  sarkoplazmatskom retikulumu. Ovo vezanje uzrokuje oslobađanje kalcija kroz RYR2 iz sarkoplazmatskog retikuluma u citosol, gdje se veže za C domen   troponina, koji pomiče tropomiozin i omogućava miozinskim ATPazama da se vežu za aktin, omogućavajući kontrakciju srčanog mišića.[9] RYR2 kanali povezani su s mnogim ćelijskim funkcijama, uključujući metabolizam mitohondrija, ekspresiju gena i preživljavanje ćelija, pored njihove uloge u kontrakciji kardiomiocita.[10]

Klinički značaj

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Štetne mutacije porodice receptora za rijanodine, a posebno receptora RYR2, dovode do patoloških konstelacija koje dovode i do akutne i do hronične srčane insuficijencije, opće poznatih kao rijanopatije.[11]

Mutacije u genu RYR2 povezane su sa kateholaminergijske polimorfna komorsksna tahikardija i aritmogena displazija desne komore.[12]

Nedavno je iznenadna srčana smrt kod nekoliko mladih osoba u zajednici Amiša (od kojih su četiri iz iste porodice) pronađeno homozigotno umnožavanje mutantnog gena RyR2.[13] Normalni (divlji tip) RyR2 funkcionira prvenstveno u srčanom mišiću.

Miševi s genetički reduciranim RYR2 pokazuju niži bazni puls i fatalne aritmije.[14]

Interakcije

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Pokazano je da receptor za riijanodin 2 ima interakcije sa:

Također pogledajte

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Reference

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000198626 - Ensembl, maj 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000021313 - Ensembl, maj 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.
  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): 13472–83. doi:10.1016/S0021-9258(18)77371-7. PMID 2380170.
  6. ^ 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.
  7. ^ Tiso N, Stephan DA, Nava A, Bagattin A, Devaney JM, Stanchi F, et al. (februar 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.
  8. ^ Guo T, Cornea RL, Huke S, Camors E, Yang Y, Picht E, et al. (juni 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.
  9. ^ "Q92736 - RYR2_HUMAN".
  10. ^ Bround MJ, Wambolt R, Luciani DS, Kulpa JE, Rodrigues B, Brownsey RW, et al. (juni 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.
  11. ^ Belevych AE, Radwański PB, Carnes CA, Györke S (maj 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.
  12. ^ "Entrez Gene: RYR2 ryanodine receptor 2 (cardiac)".
  13. ^ Tester DJ, Bombei HM, Fitzgerald KK, Giudicessi JR, Pitel BA, Thorland EC, et al. (januar 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.
  14. ^ Bround MJ, Asghari P, Wambolt RB, Bohunek L, Smits C, Philit M, et al. (decembar 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.
  15. ^ a b c d Marx SO, Reiken S, Hisamatsu Y, Jayaraman T, Burkhoff D, Rosemblit N, Marks AR (maj 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.
  16. ^ Marx SO, Reiken S, Hisamatsu Y, Gaburjakova M, Gaburjakova J, Yang YM, et al. (maj 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.
  17. ^ Meyers MB, Pickel VM, Sheu SS, Sharma VK, Scotto KW, Fishman GI (novembar 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.

Dopunska literatura

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Vanjski linkovi

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