Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPHGZ19)

• DOT Name: Inositol 1,4,5-trisphosphate receptor type 2 (ITPR2)
• Synonyms: IP3 receptor isoform 2; IP3R 2; InsP3R2; Type 2 inositol 1,4,5-trisphosphate receptor; Type 2 InsP3 receptor
• Gene Name: ITPR2
• Related Disease: Isolated anhidrosis with normal sweat glands
• UniProt ID: ITPR2_HUMAN
• Pfam ID: PF08709 ; PF00520 ; PF02815 ; PF08454 ; PF01365
• Sequence:
  MTEKMSSFLYIGDIVSLYAEGSVNGFISTLGLVDDRCVVHPEAGDLANPPKKFRDCLFKV
  CPMNRYSAQKQYWKAKQAKQGNHTEAALLKKLQHAAELEQKQNESENKKLLGEIVKYSNV
  IQLLHIKSNKYLTVNKRLPALLEKNAMRVSLDAAGNEGSWFYIHPFWKLRSEGDNIVVGD
  KVVLMPVNAGQPLHASNIELLDNPGCKEVNAVNCNTSWKITLFMKYSSYREDVLKGGDVV
  RLFHAEQEKFLTCDEYEKKQHIFLRTTLRQSATSATSSKALWEIEVVHHDPCRGGAGQWN
  SLFRFKHLATGNYLAAELNPDYRDAQNEGKNVRDGVPPTSKKKRQAGEKIMYTLVSVPHG
  NDIASLFELDATTLQRADCLVPRNSYVRLRHLCTNTWVTSTSIPIDTDEERPVMLKIGTC
  QTKEDKEAFAIVSVPLSEVRDLDFANDANKVLATTVKKLENGTITQNERRFVTKLLEDLI
  FFVADVPNNGQEVLDVVITKPNRERQKLMREQNILAQVFGILKAPFKEKAGEGSMLRLED
  LGDQRYAPYKYMLRLCYRVLRHSQQDYRKNQEYIAKNFCVMQSQIGYDILAEDTITALLH
  NNRKLLEKHITAKEIETFVSLLRRNREPRFLDYLSDLCVSNTTAIPVTQELICKFMLSPG
  NADILIQTKVVSMQADNPMESSILSDDIDDEEVWLYWIDSNKEPHGKAIRHLAQEAKEGT
  KADLEVLTYYRYQLNLFARMCLDRQYLAINQISTQLSVDLILRCVSDESLPFDLRASFCR
  LMLHMHVDRDPQESVVPVRYARLWTEIPTKITIHEYDSITDSSRNDMKRKFALTMEFVEE
  YLKEVVNQPFPFGDKEKNKLTFEVVHLARNLIYFGFYSFSELLRLTRTLLAILDIVQAPM
  SSYFERLSKFQDGGNNVMRTIHGVGEMMTQMVLSRGSIFPMSVPDVPPSIHPSKQGSPTE
  HEDVTVMDTKLKIIEILQFILSVRLDYRISYMLSIYKKEFGEDNDNAETSASGSPDTLLP
  SAIVPDIDEIAAQAETMFAGRKEKNPVQLDDEGGRTFLRVLIHLIMHDYPPLLSGALQLL
  FKHFSQRAEVLQAFKQVQLLVSNQDVDNYKQIKADLDQLRLTVEKSELWVEKSSNYENGE
  IGESQVKGGEEPIEESNILSPVQDGTKKPQIDSNKSNNYRIVKEILIRLSKLCVQNKKCR
  NQHQRLLKNMGAHSVVLDLLQIPYEKNDEKMNEVMNLAHTFLQNFCRGNPQNQVLLHKHL
  NLFLTPGLLEAETMRHIFMNNYHLCNEISERVVQHFVHCIETHGRHVEYLRFLQTIVKAD
  GKYVKKCQDMVMTELINGGEDVLIFYNDRASFPILLHMMCSERDRGDESGPLAYHITLVE
  LLAACTEGKNVYTEIKCNSLLPLDDIVRVVTHDDCIPEVKIAYVNFVNHCYVDTEVEMKE
  IYTSNHIWKLFENFLVDMARVCNTTTDRKHADIFLEKCVTESIMNIVSGFFNSPFSDNST
  SLQTHQPVFIQLLQSAFRIYNCTWPNPAQKASVESCIRTLAEVAKNRGIAIPVDLDSQVN
  TLFMKSHSNMVQRAAMGWRLSARSGPRFKEALGGPAWDYRNIIEKLQDVVASLEHQFSPM
  MQAEFSVLVDVLYSPELLFPEGSDARIRCGAFMSKLINHTKKLMEKEEKLCIKILQTLRE
  MLEKKDSFVEEGNTLRKILLNRYFKGDYSIGVNGHLSGAYSKTAQVGGSFSGQDSDKMGI
  SMSDIQCLLDKEGASELVIDVIVNTKNDRIFSEGIFLGIALLEGGNTQTQYSFYQQLHEQ
  KKSEKFFKVLYDRMKAAQKEIRSTVTVNTIDLGNKKRDDDNELMTSGPRMRVRDSTLHLK
  EGMKGQLTEASSATSKAYCVYRREMDPEIDIMCTGPEAGNTEEKSAEEVTMSPAIAIMQP
  ILRFLQLLCENHNRELQNFLRNQNNKTNYNLVCETLQFLDCICGSTTGGLGLLGLYINEK
  NVALVNQNLESLTEYCQGPCHENQTCIATHESNGIDIIIALILNDINPLGKYRMDLVLQL
  KNNASKLLLAIMESRHDSENAERILFNMRPRELVDVMKNAYNQGLECDHGDDEGGDDGVS
  PKDVGHNIYILAHQLARHNKLLQQMLKPGSDPDEGDEALKYYANHTAQIEIVRHDRTMEQ
  IVFPVPNICEYLTRESKCRVFNTTERDEQGSKVNDFFQQTEDLYNEMKWQKKIRNNPALF
  WFSRHISLWGSISFNLAVFINLAVALFYPFGDDGDEGTLSPLFSVLLWIAVAICTSMLFF
  FSKPVGIRPFLVSIMLRSIYTIGLGPTLILLGAANLCNKIVFLVSFVGNRGTFTRGYRAV
  ILDMAFLYHVAYVLVCMLGLFVHEFFYSFLLFDLVYREETLLNVIKSVTRNGRSIILTAV
  LALILVYLFSIIGFLFLKDDFTMEVDRLKNRTPVTGSHQVPTMTLTTMMEACAKENCSPT
  IPASNTADEEYEDGIERTCDTLLMCIVTVLNQGLRNGGGVGDVLRRPSKDEPLFAARVVY
  DLLFYFIVIIIVLNLIFGVIIDTFADLRSEKQKKEEILKTTCFICGLERDKFDNKTVSFE
  EHIKSEHNMWHYLYFIVLVKVKDPTEYTGPESYVAQMIVEKNLDWFPRMRAMSLVSNEGD
  SEQNEIRSLQEKLESTMSLVKQLSGQLAELKEQMTEQRKNKQRLGFLGSNTPHVNHHMPP
  H
• Function: Receptor for inositol 1,4,5-trisphosphate, a second messenger that mediates the release of intracellular calcium. This release is regulated by cAMP both dependently and independently of PKA.
• Tissue Specificity: Isoform Short is found in skeletal muscle and heart.
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  cGMP-PKG sig.ling pathway (hsa04022)
  Phosphatidylinositol sig.ling system (hsa04070)
  Oocyte meiosis (hsa04114)
  Apoptosis (hsa04210)
  Cellular senescence (hsa04218)
  Vascular smooth muscle contraction (hsa04270)
  Apelin sig.ling pathway (hsa04371)
  Osteoclast differentiation (hsa04380)
  Gap junction (hsa04540)
  Platelet activation (hsa04611)
  NOD-like receptor sig.ling pathway (hsa04621)
  C-type lectin receptor sig.ling pathway (hsa04625)
  Long-term potentiation (hsa04720)
  Retrograde endocan.binoid sig.ling (hsa04723)
  Glutamatergic sy.pse (hsa04724)
  Cholinergic sy.pse (hsa04725)
  Serotonergic sy.pse (hsa04726)
  Dopaminergic sy.pse (hsa04728)
  Long-term depression (hsa04730)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  GnRH sig.ling pathway (hsa04912)
  Estrogen sig.ling pathway (hsa04915)
  Thyroid hormone synthesis (hsa04918)
  Oxytocin sig.ling pathway (hsa04921)
  Glucagon sig.ling pathway (hsa04922)
  Renin secretion (hsa04924)
  Aldosterone synthesis and secretion (hsa04925)
  Cortisol synthesis and secretion (hsa04927)
  Parathyroid hormone synthesis, secretion and action (hsa04928)
  GnRH secretion (hsa04929)
  Cushing syndrome (hsa04934)
  Growth hormone synthesis, secretion and action (hsa04935)
  Salivary secretion (hsa04970)
  Gastric acid secretion (hsa04971)
  Pancreatic secretion (hsa04972)
  Alzheimer disease (hsa05010)
  Parkinson disease (hsa05012)
  Spinocerebellar ataxia (hsa05017)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Shigellosis (hsa05131)
  Human cytomegalovirus infection (hsa05163)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Human immunodeficiency virus 1 infection (hsa05170)
  Proteoglycans in cancer (hsa05205)
• Reactome Pathway:
  Effects of PIP2 hydrolysis (R-HSA-114508)
  Elevation of cytosolic Ca2+ levels (R-HSA-139853)
  DAG and IP3 signaling (R-HSA-1489509)
  Role of phospholipids in phagocytosis (R-HSA-2029485)
  FCERI mediated Ca+2 mobilization (R-HSA-2871809)
  Glucagon-like Peptide-1 (GLP1) regulates insulin secretion (R-HSA-381676)
  Ca2+ pathway (R-HSA-4086398)
  Regulation of insulin secretion (R-HSA-422356)
  VEGFR2 mediated cell proliferation (R-HSA-5218921)
  Ion homeostasis (R-HSA-5578775)
  CLEC7A (Dectin-1) induces NFAT activation (R-HSA-5607763)
  FCGR3A-mediated IL10 synthesis (R-HSA-9664323)
  Antigen activates B Cell Receptor (BCR) leading to generation of second messengers (R-HSA-983695)
  PLC beta mediated events (R-HSA-112043)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Isolated anhidrosis with normal sweat glands	DIS6XLEB	Supportive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Inositol 1,4,5-trisphosphate receptor type 2 (ITPR2).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Inositol 1,4,5-trisphosphate receptor type 2 (ITPR2).	[8]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Inositol 1,4,5-trisphosphate receptor type 2 (ITPR2).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Inositol 1,4,5-trisphosphate receptor type 2 (ITPR2).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Inositol 1,4,5-trisphosphate receptor type 2 (ITPR2).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Inositol 1,4,5-trisphosphate receptor type 2 (ITPR2).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Inositol 1,4,5-trisphosphate receptor type 2 (ITPR2).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Inositol 1,4,5-trisphosphate receptor type 2 (ITPR2).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Inositol 1,4,5-trisphosphate receptor type 2 (ITPR2).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Inositol 1,4,5-trisphosphate receptor type 2 (ITPR2).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Inositol 1,4,5-trisphosphate receptor type 2 (ITPR2).	[10]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Inositol 1,4,5-trisphosphate receptor type 2 (ITPR2).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Inositol 1,4,5-trisphosphate receptor type 2 (ITPR2).	[12]
Marinol	DM70IK5	Approved	Marinol increases the expression of Inositol 1,4,5-trisphosphate receptor type 2 (ITPR2).	[13]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Inositol 1,4,5-trisphosphate receptor type 2 (ITPR2).	[14]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Inositol 1,4,5-trisphosphate receptor type 2 (ITPR2).	[16]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Inositol 1,4,5-trisphosphate receptor type 2 (ITPR2).	[17]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Inositol 1,4,5-trisphosphate receptor type 2 (ITPR2).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Inositol 1,4,5-trisphosphate receptor type 2 (ITPR2).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Inositol 1,4,5-trisphosphate receptor type 2 (ITPR2).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Inositol 1,4,5-trisphosphate receptor type 2 (ITPR2).	[22]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Inositol 1,4,5-trisphosphate receptor type 2 (ITPR2).	[23]

References

• [1] Abolished InsP3R2 function inhibits sweat secretion in both humans and mice. J Clin Invest. 2014 Nov;124(11):4773-80. doi: 10.1172/JCI70720. Epub 2014 Oct 20.
• [2] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [3] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [4] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [5] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [9] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [10] Arsenic targets Pin1 and cooperates with retinoic acid to inhibit cancer-driving pathways and tumor-initiating cells. Nat Commun. 2018 Aug 9;9(1):3069. doi: 10.1038/s41467-018-05402-2.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [13] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [14] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [15] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [16] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [17] Epigallocatechin-3-gallate (EGCG) protects against chromate-induced toxicity in vitro. Toxicol Appl Pharmacol. 2012 Jan 15;258(2):166-75.
• [18] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [19] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [20] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [23] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.