Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0PF19E)

• DOT Name: Ryanodine receptor 2 (RYR2)
• Synonyms: RYR-2; RyR2; hRYR-2; Cardiac muscle ryanodine receptor; Cardiac muscle ryanodine receptor-calcium release channel; Type 2 ryanodine receptor
• Gene Name: RYR2
• Related Disease:
  Catecholaminergic polymorphic ventricular tachycardia
  Catecholaminergic polymorphic ventricular tachycardia 1
  Obsolete arrhythmogenic right ventricular dysplasia 2
  Alzheimer disease
  Asthma
  Astrocytoma
  Atrial fibrillation
  Autism
  Cardiac disease
  Cardiac failure
  Cardiovascular disease
  Congestive heart failure
  Coronary atherosclerosis
  Coronary heart disease
  Dilated cardiomyopathy
  Dilated cardiomyopathy 1A
  Epilepsy
  Head and neck carcinoma
  Head-neck squamous cell carcinoma
  High blood pressure
  Malignant hyperthermia of anesthesia
  Malignant mesothelioma
  Melanoma
  Myocardial ischemia
  Narcolepsy
  Polymorphic ventricular tachycardia
  Thyroid gland carcinoma
  Ventricular fibrillation
  Autism spectrum disorder
  Catecholaminergic polymorphic ventricular tachycardia 2
  Long QT syndrome
  Neoplasm
  Ventricular tachycardia
  Ventricular tachycardia, familial
  Andersen-Tawil syndrome
  Brugada syndrome
  Cardiomyopathy
  Central core myopathy
  Hepatocellular carcinoma
  Hypertrophic cardiomyopathy
  Intellectual disability
  Myocardial infarction
  Neuroblastoma
  Non-insulin dependent diabetes
  Obesity
  Paroxysmal familial ventricular fibrillation
  Type-1/2 diabetes
  Arrhythmogenic right ventricular cardiomyopathy
• UniProt ID: RYR2_HUMAN
• PDB ID: 4JKQ; 6Y4O; 6Y4P; 7KL5; 7U9Q; 7U9R; 7U9T; 7U9X; 7U9Z; 7UA1; 7UA3; 7UA4; 7UA5; 7UA9; 8UQ2; 8UQ3; 8UQ4; 8UQ5; 8UXC; 8UXE; 8UXF; 8UXG; 8UXH; 8UXI; 8UXL; 8UXM
• Pfam ID: PF13499 ; PF08709 ; PF00520 ; PF02815 ; PF08454 ; PF06459 ; PF01365 ; PF21119 ; PF02026 ; PF00622
• Sequence:
  MADGGEGEDEIQFLRTDDEVVLQCTATIHKEQQKLCLAAEGFGNRLCFLESTSNSKNVPP
  DLSICTFVLEQSLSVRALQEMLANTVEKSEGQVDVEKWKFMMKTAQGGGHRTLLYGHAIL
  LRHSYSGMYLCCLSTSRSSTDKLAFDVGLQEDTTGEACWWTIHPASKQRSEGEKVRVGDD
  LILVSVSSERYLHLSYGNGSLHVDAAFQQTLWSVAPISSGSEAAQGYLIGGDVLRLLHGH
  MDECLTVPSGEHGEEQRRTVHYEGGAVSVHARSLWRLETLRVAWSGSHIRWGQPFRLRHV
  TTGKYLSLMEDKNLLLMDKEKADVKSTAFTFRSSKEKLDVGVRKEVDGMGTSEIKYGDSV
  CYIQHVDTGLWLTYQSVDVKSVRMGSIQRKAIMHHEGHMDDGISLSRSQHEESRTARVIR
  STVFLFNRFIRGLDALSKKAKASTVDLPIESVSLSLQDLIGYFHPPDEHLEHEDKQNRLR
  ALKNRQNLFQEEGMINLVLECIDRLHVYSSAAHFADVAGREAGESWKSILNSLYELLAAL
  IRGNRKNCAQFSGSLDWLISRLERLEASSGILEVLHCVLVESPEALNIIKEGHIKSIISL
  LDKHGRNHKVLDVLCSLCVCHGVAVRSNQHLICDNLLPGRDLLLQTRLVNHVSSMRPNIF
  LGVSEGSAQYKKWYYELMVDHTEPFVTAEATHLRVGWASTEGYSPYPGGGEEWGGNGVGD
  DLFSYGFDGLHLWSGCIARTVSSPNQHLLRTDDVISCCLDLSAPSISFRINGQPVQGMFE
  NFNIDGLFFPVVSFSAGIKVRFLLGGRHGEFKFLPPPGYAPCYEAVLPKEKLKVEHSREY
  KQERTYTRDLLGPTVSLTQAAFTPIPVDTSQIVLPPHLERIREKLAENIHELWVMNKIEL
  GWQYGPVRDDNKRQHPCLVEFSKLPEQERNYNLQMSLETLKTLLALGCHVGISDEHAEDK
  VKKMKLPKNYQLTSGYKPAPMDLSFIKLTPSQEAMVDKLAENAHNVWARDRIRQGWTYGI
  QQDVKNRRNPRLVPYTLLDDRTKKSNKDSLREAVRTLLGYGYNLEAPDQDHAARAEVCSG
  TGERFRIFRAEKTYAVKAGRWYFEFETVTAGDMRVGWSRPGCQPDQELGSDERAFAFDGF
  KAQRWHQGNEHYGRSWQAGDVVGCMVDMNEHTMMFTLNGEILLDDSGSELAFKDFDVGDG
  FIPVCSLGVAQVGRMNFGKDVSTLKYFTICGLQEGYEPFAVNTNRDITMWLSKRLPQFLQ
  VPSNHEHIEVTRIDGTIDSSPCLKVTQKSFGSQNSNTDIMFYRLSMPIECAEVFSKTVAG
  GLPGAGLFGPKNDLEDYDADSDFEVLMKTAHGHLVPDRVDKDKEATKPEFNNHKDYAQEK
  PSRLKQRFLLRRTKPDYSTSHSARLTEDVLADDRDDYDFLMQTSTYYYSVRIFPGQEPAN
  VWVGWITSDFHQYDTGFDLDRVRTVTVTLGDEKGKVHESIKRSNCYMVCAGESMSPGQGR
  NNNGLEIGCVVDAASGLLTFIANGKELSTYYQVEPSTKLFPAVFAQATSPNVFQFELGRI
  KNVMPLSAGLFKSEHKNPVPQCPPRLHVQFLSHVLWSRMPNQFLKVDVSRISERQGWLVQ
  CLDPLQFMSLHIPEENRSVDILELTEQEELLKFHYHTLRLYSAVCALGNHRVAHALCSHV
  DEPQLLYAIENKYMPGLLRAGYYDLLIDIHLSSYATARLMMNNEYIVPMTEETKSITLFP
  DENKKHGLPGIGLSTSLRPRMQFSSPSFVSISNECYQYSPEFPLDILKSKTIQMLTEAVK
  EGSLHARDPVGGTTEFLFVPLIKLFYTLLIMGIFHNEDLKHILQLIEPSVFKEAATPEEE
  SDTLEKELSVDDAKLQGAGEEEAKGGKRPKEGLLQMKLPEPVKLQMCLLLQYLCDCQVRH
  RIEAIVAFSDDFVAKLQDNQRFRYNEVMQALNMSAALTARKTKEFRSPPQEQINMLLNFK
  DDKSECPCPEEIRDQLLDFHEDLMTHCGIELDEDGSLDGNSDLTIRGRLLSLVEKVTYLK
  KKQAEKPVESDSKKSSTLQQLISETMVRWAQESVIEDPELVRAMFVLLHRQYDGIGGLVR
  ALPKTYTINGVSVEDTINLLASLGQIRSLLSVRMGKEEEKLMIRGLGDIMNNKVFYQHPN
  LMRALGMHETVMEVMVNVLGGGESKEITFPKMVANCCRFLCYFCRISRQNQKAMFDHLSY
  LLENSSVGLASPAMRGSTPLDVAAASVMDNNELALALREPDLEKVVRYLAGCGLQSCQML
  VSKGYPDIGWNPVEGERYLDFLRFAVFCNGESVEENANVVVRLLIRRPECFGPALRGEGG
  NGLLAAMEEAIKIAEDPSRDGPSPNSGSSKTLDTEEEEDDTIHMGNAIMTFYSALIDLLG
  RCAPEMHLIHAGKGEAIRIRSILRSLIPLGDLVGVISIAFQMPTIAKDGNVVEPDMSAGF
  CPDHKAAMVLFLDRVYGIEVQDFLLHLLEVGFLPDLRAAASLDTAALSATDMALALNRYL
  CTAVLPLLTRCAPLFAGTEHHASLIDSLLHTVYRLSKGCSLTKAQRDSIEVCLLSICGQL
  RPSMMQHLLRRLVFDVPLLNEHAKMPLKLLTNHYERCWKYYCLPGGWGNFGAASEEELHL
  SRKLFWGIFDALSQKKYEQELFKLALPCLSAVAGALPPDYMESNYVSMMEKQSSMDSEGN
  FNPQPVDTSNITIPEKLEYFINKYAEHSHDKWSMDKLANGWIYGEIYSDSSKVQPLMKPY
  KLLSEKEKEIYRWPIKESLKTMLAWGWRIERTREGDSMALYNRTRRISQTSQVSVDAAHG
  YSPRAIDMSNVTLSRDLHAMAEMMAENYHNIWAKKKKMELESKGGGNHPLLVPYDTLTAK
  EKAKDREKAQDILKFLQINGYAVSRGFKDLELDTPSIEKRFAYSFLQQLIRYVDEAHQYI
  LEFDGGSRGKGEHFPYEQEIKFFAKVVLPLIDQYFKNHRLYFLSAASRPLCSGGHASNKE
  KEMVTSLFCKLGVLVRHRISLFGNDATSIVNCLHILGQTLDARTVMKTGLESVKSALRAF
  LDNAAEDLEKTMENLKQGQFTHTRNQPKGVTQIINYTTVALLPMLSSLFEHIGQHQFGED
  LILEDVQVSCYRILTSLYALGTSKSIYVERQRSALGECLAAFAGAFPVAFLETHLDKHNI
  YSIYNTKSSRERAALSLPTNVEDVCPNIPSLEKLMEEIVELAESGIRYTQMPHVMEVILP
  MLCSYMSRWWEHGPENNPERAEMCCTALNSEHMNTLLGNILKIIYNNLGIDEGAWMKRLA
  VFSQPIINKVKPQLLKTHFLPLMEKLKKKAATVVSEEDHLKAEARGDMSEAELLILDEFT
  TLARDLYAFYPLLIRFVDYNRAKWLKEPNPEAEELFRMVAEVFIYWSKSHNFKREEQNFV
  VQNEINNMSFLITDTKSKMSKAAVSDQERKKMKRKGDRYSMQTSLIVAALKRLLPIGLNI
  CAPGDQELIALAKNRFSLKDTEDEVRDIIRSNIHLQGKLEDPAIRWQMALYKDLPNRTDD
  TSDPEKTVERVLDIANVLFHLEQKSKRVGRRHYCLVEHPQRSKKAVWHKLLSKQRKRAVV
  ACFRMAPLYNLPRHRAVNLFLQGYEKSWIETEEHYFEDKLIEDLAKPGAEPPEEDEGTKR
  VDPLHQLILLFSRTALTEKCKLEEDFLYMAYADIMAKSCHDEEDDDGEEEVKSFEEKEME
  KQKLLYQQARLHDRGAAEMVLQTISASKGETGPMVAATLKLGIAILNGGNSTVQQKMLDY
  LKEKKDVGFFQSLAGLMQSCSVLDLNAFERQNKAEGLGMVTEEGSGEKVLQDDEFTCDLF
  RFLQLLCEGHNSDFQNYLRTQTGNNTTVNIIISTVDYLLRVQESISDFYWYYSGKDVIDE
  QGQRNFSKAIQVAKQVFNTLTEYIQGPCTGNQQSLAHSRLWDAVVGFLHVFAHMQMKLSQ
  DSSQIELLKELMDLQKDMVVMLLSMLEGNVVNGTIGKQMVDMLVESSNNVEMILKFFDMF
  LKLKDLTSSDTFKEYDPDGKGVISKRDFHKAMESHKHYTQSETEFLLSCAETDENETLDY
  EEFVKRFHEPAKDIGFNVAVLLTNLSEHMPNDTRLQTFLELAESVLNYFQPFLGRIEIMG
  SAKRIERVYFEISESSRTQWEKPQVKESKRQFIFDVVNEGGEKEKMELFVNFCEDTIFEM
  QLAAQISESDLNERSANKEESEKERPEEQGPRMAFFSILTVRSALFALRYNILTLMRMLS
  LKSLKKQMKKVKKMTVKDMVTAFFSSYWSIFMTLLHFVASVFRGFFRIICSLLLGGSLVE
  GAKKIKVAELLANMPDPTQDEVRGDGEEGERKPLEAALPSEDLTDLKELTEESDLLSDIF
  GLDLKREGGQYKLIPHNPNAGLSDLMSNPVPMPEVQEKFQEQKAKEEEKEEKEETKSEPE
  KAEGEDGEKEEKAKEDKGKQKLRQLHTHRYGEPEVPESAFWKKIIAYQQKLLNYFARNFY
  NMRMLALFVAFAINFILLFYKVSTSSVVEGKELPTRSSSENAKVTSLDSSSHRIIAVHYV
  LEESSGYMEPTLRILAILHTVISFFCIIGYYCLKVPLVIFKREKEVARKLEFDGLYITEQ
  PSEDDIKGQWDRLVINTQSFPNNYWDKFVKRKVMDKYGEFYGRDRISELLGMDKAALDFS
  DAREKKKPKKDSSLSAVLNSIDVKYQMWKLGVVFTDNSFLYLAWYMTMSVLGHYNNFFFA
  AHLLDIAMGFKTLRTILSSVTHNGKQLVLTVGLLAVVVYLYTVVAFNFFRKFYNKSEDGD
  TPDMKCDDMLTCYMFHMYVGVRAGGGIGDEIEDPAGDEYEIYRIIFDITFFFFVIVILLA
  IIQGLIIDAFGELRDQQEQVKEDMETKCFICGIGNDYFDTVPHGFETHTLQEHNLANYLF
  FLMYLINKDETEHTGQESYVWKMYQERCWEFFPAGDCFRKQYEDQLN
• Function: Cytosolic calcium-activated calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytosol and thereby plays a key role in triggering cardiac muscle contraction. Aberrant channel activation can lead to cardiac arrhythmia. In cardiac myocytes, calcium release is triggered by increased Ca(2+) cytosolic levels due to activation of the L-type calcium channel CACNA1C. The calcium channel activity is modulated by formation of heterotetramers with RYR3. Required for cellular calcium ion homeostasis. Required for embryonic heart development.
• Tissue Specificity: Detected in heart muscle (at protein level). Heart muscle, brain (cerebellum and hippocampus) and placenta.
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  cAMP sig.ling pathway (hsa04024)
  Cardiac muscle contraction (hsa04260)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Apelin sig.ling pathway (hsa04371)
  Circadian entrainment (hsa04713)
  Insulin secretion (hsa04911)
  Oxytocin sig.ling pathway (hsa04921)
  Pancreatic secretion (hsa04972)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Hypertrophic cardiomyopathy (hsa05410)
  Arrhythmogenic right ventricular cardiomyopathy (hsa05412)
  Dilated cardiomyopathy (hsa05414)
  Diabetic cardiomyopathy (hsa05415)
• Reactome Pathway:
  Ion homeostasis (R-HSA-5578775)
  Stimuli-sensing channels (R-HSA-2672351)

Molecular Interaction Atlas (MIA) of This DOT

48 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Catecholaminergic polymorphic ventricular tachycardia	DISSAS1A	Definitive	Autosomal dominant	[1]
Catecholaminergic polymorphic ventricular tachycardia 1	DISKGB3F	Definitive	Autosomal dominant	[2]
Obsolete arrhythmogenic right ventricular dysplasia 2	DISRV6TN	Definitive	Autosomal dominant	[3]
Alzheimer disease	DISF8S70	Strong	Biomarker	[4]
Asthma	DISW9QNS	Strong	Genetic Variation	[5]
Astrocytoma	DISL3V18	Strong	Genetic Variation	[6]
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[7]
Autism	DISV4V1Z	Strong	Biomarker	[8]
Cardiac disease	DISVO1I5	Strong	Genetic Variation	[9]
Cardiac failure	DISDC067	Strong	Biomarker	[10]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[11]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[10]
Coronary atherosclerosis	DISKNDYU	Strong	Genetic Variation	[12]
Coronary heart disease	DIS5OIP1	Strong	Genetic Variation	[12]
Dilated cardiomyopathy	DISX608J	Strong	Genetic Variation	[13]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Genetic Variation	[13]
Epilepsy	DISBB28L	Strong	Biomarker	[9]
Head and neck carcinoma	DISOU1DS	Strong	Posttranslational Modification	[14]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Genetic Variation	[14]
High blood pressure	DISY2OHH	Strong	Altered Expression	[15]
Malignant hyperthermia of anesthesia	DISYC9XI	Strong	Genetic Variation	[16]
Malignant mesothelioma	DISTHJGH	Strong	Biomarker	[17]
Melanoma	DIS1RRCY	Strong	Biomarker	[18]
Myocardial ischemia	DISFTVXF	Strong	Biomarker	[19]
Narcolepsy	DISLCNLI	Strong	Genetic Variation	[20]
Polymorphic ventricular tachycardia	DISCPO8T	Strong	Genetic Variation	[21]
Thyroid gland carcinoma	DISMNGZ0	Strong	Altered Expression	[22]
Ventricular fibrillation	DIS7IN76	Strong	Biomarker	[23]
Autism spectrum disorder	DISXK8NV	moderate	Genetic Variation	[24]
Catecholaminergic polymorphic ventricular tachycardia 2	DIS9AWAE	moderate	Genetic Variation	[25]
Long QT syndrome	DISMKWS3	moderate	Genetic Variation	[26]
Neoplasm	DISZKGEW	moderate	Altered Expression	[22]
Ventricular tachycardia	DISIBXJ3	moderate	Biomarker	[27]
Ventricular tachycardia, familial	DISYG7IE	moderate	Biomarker	[28]
Andersen-Tawil syndrome	DIS3IWZ7	Limited	Genetic Variation	[29]
Brugada syndrome	DISSGN0E	Limited	Genetic Variation	[30]
Cardiomyopathy	DISUPZRG	Limited	Biomarker	[31]
Central core myopathy	DIS18AZZ	Limited	Genetic Variation	[16]
Hepatocellular carcinoma	DIS0J828	Limited	Genetic Variation	[32]
Hypertrophic cardiomyopathy	DISQG2AI	Limited	Autosomal dominant	[1]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[33]
Myocardial infarction	DIS655KI	Limited	Biomarker	[34]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[35]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[36]
Obesity	DIS47Y1K	Limited	Biomarker	[37]
Paroxysmal familial ventricular fibrillation	DISRM7IX	Limited	Genetic Variation	[38]
Type-1/2 diabetes	DISIUHAP	Limited	Altered Expression	[39]
Arrhythmogenic right ventricular cardiomyopathy	DIS3V2BE	Refuted	Autosomal dominant	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cerivastatin	DMXCM7H	Approved	Ryanodine receptor 2 (RYR2) increases the Rhabdomyolysis ADR of Cerivastatin.	[52]

4 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Ryanodine receptor 2 (RYR2).	[40]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Ryanodine receptor 2 (RYR2).	[42]
Isoproterenol	DMK7MEY	Approved	Isoproterenol increases the phosphorylation of Ryanodine receptor 2 (RYR2).	[46]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Ryanodine receptor 2 (RYR2).	[50]

12 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ryanodine receptor 2 (RYR2).	[41]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Ryanodine receptor 2 (RYR2).	[43]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Ryanodine receptor 2 (RYR2).	[44]
Etoposide	DMNH3PG	Approved	Etoposide decreases the expression of Ryanodine receptor 2 (RYR2).	[45]
Mitoxantrone	DMM39BF	Approved	Mitoxantrone decreases the expression of Ryanodine receptor 2 (RYR2).	[41]
Daunorubicin	DMQUSBT	Approved	Daunorubicin decreases the expression of Ryanodine receptor 2 (RYR2).	[41]
Carvedilol	DMHTEAO	Approved	Carvedilol increases the activity of Ryanodine receptor 2 (RYR2).	[47]
Atenolol	DMNKG1Z	Approved	Atenolol increases the activity of Ryanodine receptor 2 (RYR2).	[47]
Metoprolol	DMOJ0V6	Approved	Metoprolol increases the activity of Ryanodine receptor 2 (RYR2).	[47]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Ryanodine receptor 2 (RYR2).	[48]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Ryanodine receptor 2 (RYR2).	[49]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Ryanodine receptor 2 (RYR2).	[51]

References

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• [3] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
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• [10] Resiniferatoxin reduces ventricular arrhythmias in heart failure via selectively blunting cardiac sympathetic afferent projection into spinal cord in rats.Eur J Pharmacol. 2020 Jan 15;867:172836. doi: 10.1016/j.ejphar.2019.172836. Epub 2019 Dec 4.
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