Details of Drug Off-Target (DOT)

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

• DOT Name: Transient receptor potential cation channel subfamily V member 4 (TRPV4)
• Synonyms: TrpV4; Osm-9-like TRP channel 4; OTRPC4; Transient receptor potential protein 12; TRP12; Vanilloid receptor-like channel 2; Vanilloid receptor-like protein 2; VRL-2; Vanilloid receptor-related osmotically-activated channel; VR-OAC
• Gene Name: TRPV4
• Related Disease:
  Metatropic dysplasia
  Neuromuscular disease
  Spondylometaphyseal dysplasia, Kozlowski type
  TRPV4-related bone disorder
  Autosomal dominant brachyolmia
  Charcot-Marie-Tooth disease axonal type 2C
  Scapuloperoneal spinal muscular atrophy, autosomal dominant
  Familial avascular necrosis of femoral head
  Familial digital arthropathy-brachydactyly
  Neuronopathy, distal hereditary motor, autosomal dominant 8
  Parastremmatic dwarfism
• UniProt ID: TRPV4_HUMAN
• PDB ID: 4DX1; 4DX2; 7AA5; 8FC7; 8FC8; 8FC9; 8FCA; 8FCB; 8T1B; 8T1C; 8T1D; 8T1E; 8T1F
• Pfam ID: PF00023 ; PF00520
• Sequence:
  MADSSEGPRAGPGEVAELPGDESGTPGGEAFPLSSLANLFEGEDGSLSPSPADASRPAGP
  GDGRPNLRMKFQGAFRKGVPNPIDLLESTLYESSVVPGPKKAPMDSLFDYGTYRHHSSDN
  KRWRKKIIEKQPQSPKAPAPQPPPILKVFNRPILFDIVSRGSTADLDGLLPFLLTHKKRL
  TDEEFREPSTGKTCLPKALLNLSNGRNDTIPVLLDIAERTGNMREFINSPFRDIYYRGQT
  ALHIAIERRCKHYVELLVAQGADVHAQARGRFFQPKDEGGYFYFGELPLSLAACTNQPHI
  VNYLTENPHKKADMRRQDSRGNTVLHALVAIADNTRENTKFVTKMYDLLLLKCARLFPDS
  NLEAVLNNDGLSPLMMAAKTGKIGIFQHIIRREVTDEDTRHLSRKFKDWAYGPVYSSLYD
  LSSLDTCGEEASVLEILVYNSKIENRHEMLAVEPINELLRDKWRKFGAVSFYINVVSYLC
  AMVIFTLTAYYQPLEGTPPYPYRTTVDYLRLAGEVITLFTGVLFFFTNIKDLFMKKCPGV
  NSLFIDGSFQLLYFIYSVLVIVSAALYLAGIEAYLAVMVFALVLGWMNALYFTRGLKLTG
  TYSIMIQKILFKDLFRFLLVYLLFMIGYASALVSLLNPCANMKVCNEDQTNCTVPTYPSC
  RDSETFSTFLLDLFKLTIGMGDLEMLSSTKYPVVFIILLVTYIILTFVLLLNMLIALMGE
  TVGQVSKESKHIWKLQWATTILDIERSFPVFLRKAFRSGEMVTVGKSSDGTPDRRWCFRV
  DEVNWSHWNQNLGIINEDPGKNETYQYYGFSHTVGRLRRDRWSSVVPRVVELNKNSNPDE
  VVVPLDSMGNPRCDGHQQGYPRKWRTDDAPL
• Function: Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity. Activation by exposure to hypotonicity within the physiological range exhibits an outward rectification. Also activated by heat, low pH, citrate and phorbol esters. Increase of intracellular Ca(2+) potentiates currents. Channel activity seems to be regulated by a calmodulin-dependent mechanism with a negative feedback mechanism. Promotes cell-cell junction formation in skin keratinocytes and plays an important role in the formation and/or maintenance of functional intercellular barriers. Acts as a regulator of intracellular Ca(2+) in synoviocytes. Plays an obligatory role as a molecular component in the nonselective cation channel activation induced by 4-alpha-phorbol 12,13-didecanoate and hypotonic stimulation in synoviocytes and also regulates production of IL-8. Together with PKD2, forms mechano- and thermosensitive channels in cilium. Negatively regulates expression of PPARGC1A, UCP1, oxidative metabolism and respiration in adipocytes. Regulates expression of chemokines and cytokines related to pro-inflammatory pathway in adipocytes. Together with AQP5, controls regulatory volume decrease in salivary epithelial cells. Required for normal development and maintenance of bone and cartilage. In its inactive state, may sequester DDX3X at the plasma membrane. When activated, the interaction between both proteins is affected and DDX3X relocalizes to the nucleus. In neurons of the central nervous system, could play a role in triggering voluntary water intake in response to increased sodium concentration in body fluid; [Isoform 1]: Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity. Activation by exposure to hypotonicity within the physiological range exhibits an outward rectification. Also activated by phorbol esters. Has the same channel activity as isoform 1, and is activated by the same stimuli; [Isoform 5]: Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity. Activation by exposure to hypotonicity within the physiological range exhibits an outward rectification. Also activated by phorbol esters. Has the same channel activity as isoform 1, and is activated by the same stimuli; [Isoform 2]: Lacks channel activity, due to impaired oligomerization and intracellular retention; [Isoform 4]: Lacks channel activity, due to impaired oligomerization and intracellular retention; [Isoform 6]: Lacks channel activity, due to impaired oligomerization and intracellular retention; (Microbial infection) Facilitates hepatitis C virus (HCV) replication, possibly through its action on DDX3X; (Microbial infection) Facilitates Dengue virus (DENV) replication, possibly through its action on DDX3X; (Microbial infection) Facilitates Zika virus (ZIKV) replication, possibly through its action on DDX3X.
• Tissue Specificity: Found in the synoviocytes from patients with (RA) and without (CTR) rheumatoid arthritis (at protein level).
• KEGG Pathway:
  Cellular senescence (hsa04218)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway: TRP channels (R-HSA-3295583)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Metatropic dysplasia	DISXWLS8	Definitive	Autosomal dominant	[1]
Neuromuscular disease	DISQTIJZ	Definitive	Autosomal dominant	[2]
Spondylometaphyseal dysplasia, Kozlowski type	DISUS1OV	Definitive	Autosomal dominant	[1]
TRPV4-related bone disorder	DISRJWLL	Definitive	Autosomal dominant	[2]
Autosomal dominant brachyolmia	DISSFZ25	Strong	Autosomal dominant	[3]
Charcot-Marie-Tooth disease axonal type 2C	DIS1S5NJ	Strong	Autosomal dominant	[4]
Scapuloperoneal spinal muscular atrophy, autosomal dominant	DISCOCGI	Moderate	Autosomal dominant	[5]
Familial avascular necrosis of femoral head	DIS1X75T	Supportive	Autosomal dominant	[6]
Familial digital arthropathy-brachydactyly	DIS79NS3	Supportive	Autosomal dominant	[7]
Neuronopathy, distal hereditary motor, autosomal dominant 8	DISYKBMQ	Supportive	Autosomal dominant	[8]
Parastremmatic dwarfism	DIS0C1VP	Supportive	Autosomal dominant	[9]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
AMG 386	DMQJXL4	Phase 3	Transient receptor potential cation channel subfamily V member 4 (TRPV4) affects the abundance of AMG 386.	[17]

6 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 Transient receptor potential cation channel subfamily V member 4 (TRPV4).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Transient receptor potential cation channel subfamily V member 4 (TRPV4).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Transient receptor potential cation channel subfamily V member 4 (TRPV4).	[12]
Cannabidiol	DM0659E	Approved	Cannabidiol affects the activity of Transient receptor potential cation channel subfamily V member 4 (TRPV4).	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Transient receptor potential cation channel subfamily V member 4 (TRPV4).	[15]
Arachidonic acid	DMUOQZD	Investigative	Arachidonic acid increases the activity of Transient receptor potential cation channel subfamily V member 4 (TRPV4).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Transient receptor potential cation channel subfamily V member 4 (TRPV4).	[14]

References

• [1] Mutations in the gene encoding the calcium-permeable ion channel TRPV4 produce spondylometaphyseal dysplasia, Kozlowski type and metatropic dysplasia. Am J Hum Genet. 2009 Mar;84(3):307-15. doi: 10.1016/j.ajhg.2009.01.021. Epub 2009 Feb 19.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [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.
• [4] The gene for HMSN2C maps to 12q23-24: a region of neuromuscular disorders. Neurology. 2003 Apr 8;60(7):1151-6. doi: 10.1212/01.wnl.0000055900.30217.ea.
• [5] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [6] Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head. J Med Genet. 2016 Oct;53(10):705-9. doi: 10.1136/jmedgenet-2016-103829. Epub 2016 Jun 21.
• [7] Mutations in TRPV4 cause an inherited arthropathy of hands and feet. Nat Genet. 2011 Oct 2;43(11):1142-6. doi: 10.1038/ng.945.
• [8] Autosomal Dominant TRPV4 Disorders. 2014 May 15 [updated 2020 Sep 17]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [9] Spondylo-epiphyseal dysplasia, Maroteaux type (pseudo-Morquio syndrome type 2), and parastremmatic dysplasia are caused by TRPV4 mutations. Am J Med Genet A. 2010 Jun;152A(6):1443-9. doi: 10.1002/ajmg.a.33414.
• [10] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [11] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [12] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [13] Cannabidiol inhibits human glioma by induction of lethal mitophagy through activating TRPV4. Autophagy. 2021 Nov;17(11):3592-3606. doi: 10.1080/15548627.2021.1885203. Epub 2021 Feb 25.
• [14] 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.
• [15] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [16] Inhibition of the cation channel TRPV4 improves bladder function in mice and rats with cyclophosphamide-induced cystitis. Proc Natl Acad Sci U S A. 2010 Nov 2;107(44):19084-9.
• [17] A loss-of-function nonsynonymous polymorphism in the osmoregulatory TRPV4 gene is associated with human hyponatremia. Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):14034-9. doi: 10.1073/pnas.0904084106. Epub 2009 Aug 4.