Target General Infomation
Target ID
T64213 (Former ID: TTDR01160)
Target Name
Transient receptor potential cation channel V4 (TRPV4)
Synonyms
Vanilloid receptor-related osmotically-activated channel; Vanilloid receptor-like protein 2; Vanilloid receptor-like channel 2; VROAC; VRL2; VRL-2; VR-OAC; TrpV4; Transient receptor potential protein 12; Transient receptor potential cation channel subfamily V member 4; TRP12; Osm-9-like TRP channel 4; OTRPC4
Gene Name
TRPV4
Target Type
Clinical trial target
[1]
Disease [+] 3 Target-related Diseases +
1 Acute myeloid leukaemia [ICD-11: 2A60]
2 Heart failure [ICD-11: BD10-BD1Z]
3 Hodgkin lymphoma [ICD-11: 2B30]
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 (By similarity). 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 (By similarity). Regulates expression of chemokines and cytokines related to proinflammatory pathway in adipocytes (By similarity). Together with AQP5, controls regulatory volume decrease in salivary epithelial cells (By similarity). Required for normal development and maintenance of bone and cartilage.
BioChemical Class
Transient receptor potential catioin channel
UniProt ID
TRPV4_HUMAN
Sequence
MADSSEGPRAGPGEVAELPGDESGTPGGEAFPLSSLANLFEGEDGSLSPSPADASRPAGP
GDGRPNLRMKFQGAFRKGVPNPIDLLESTLYESSVVPGPKKAPMDSLFDYGTYRHHSSDN
KRWRKKIIEKQPQSPKAPAPQPPPILKVFNRPILFDIVSRGSTADLDGLLPFLLTHKKRL
TDEEFREPSTGKTCLPKALLNLSNGRNDTIPVLLDIAERTGNMREFINSPFRDIYYRGQT
ALHIAIERRCKHYVELLVAQGADVHAQARGRFFQPKDEGGYFYFGELPLSLAACTNQPHI
VNYLTENPHKKADMRRQDSRGNTVLHALVAIADNTRENTKFVTKMYDLLLLKCARLFPDS
NLEAVLNNDGLSPLMMAAKTGKIGIFQHIIRREVTDEDTRHLSRKFKDWAYGPVYSSLYD
LSSLDTCGEEASVLEILVYNSKIENRHEMLAVEPINELLRDKWRKFGAVSFYINVVSYLC
AMVIFTLTAYYQPLEGTPPYPYRTTVDYLRLAGEVITLFTGVLFFFTNIKDLFMKKCPGV
NSLFIDGSFQLLYFIYSVLVIVSAALYLAGIEAYLAVMVFALVLGWMNALYFTRGLKLTG
TYSIMIQKILFKDLFRFLLVYLLFMIGYASALVSLLNPCANMKVCNEDQTNCTVPTYPSC
RDSETFSTFLLDLFKLTIGMGDLEMLSSTKYPVVFIILLVTYIILTFVLLLNMLIALMGE
TVGQVSKESKHIWKLQWATTILDIERSFPVFLRKAFRSGEMVTVGKSSDGTPDRRWCFRV
DEVNWSHWNQNLGIINEDPGKNETYQYYGFSHTVGRLRRDRWSSVVPRVVELNKNSNPDE
VVVPLDSMGNPRCDGHQQGYPRKWRTDDAPL
Drugs and Modes of Action
Clinical Trial Drug(s) [+] 2 Clinical Trial Drugs +
1 GSK2798745 Drug Info Phase 2 Heart failure [2], [3]
2 phorbol 12-myristate 13-acetate Drug Info Phase 2 Acute myeloid leukaemia [4]
Mode of Action [+] 4 Modes of Action +
Antagonist [+] 1 Antagonist drugs +
1 GSK2798745 Drug Info [2], [3]
Activator [+] 8 Activator drugs +
1 phorbol 12-myristate 13-acetate Drug Info [1]
2 4alpha-PDD Drug Info [1]
3 4alpha-PDH Drug Info [6]
4 5,6-epoxyeicosatrienoic acid Drug Info [7]
5 bisandrographolide Drug Info [8]
6 citric acid Drug Info [10]
7 GSK1016790A Drug Info [11]
8 RN1747 Drug Info [15]
Inhibitor [+] 6 Inhibitor drugs +
1 4-Pyridin-2-yl-piperazine-1-carboxylic acid amide Drug Info [5]
2 5'-iodoresiniferatoxin Drug Info [5]
3 CAPSAZEPINE Drug Info [9]
4 MK-056 Drug Info [14]
5 Pyrrolidin-1-yl-thiourea Drug Info [5]
6 SC-0030 Drug Info [14]
Blocker (channel blocker) [+] 3 Blocker (channel blocker) drugs +
1 GSK2193874 Drug Info [12]
2 HC067047 Drug Info [13]
3 RN1734 Drug Info [15]
Target Affiliated Biological Pathways
KEGG Pathway [+] 1 KEGG Pathways +
1 Inflammatory mediator regulation of TRP channels
Reactome [+] 1 Reactome Pathways +
1 TRP channels
Target-Related Models and Studies
Target Validation
References
REF 1 Activation of TRPV4 channels (hVRL-2/mTRP12) by phorbol derivatives. J Biol Chem. 2002 Apr 19;277(16):13569-77.
REF 2 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
REF 3 Antibodies and venom peptides: new modalities for ion channels. Nat Rev Drug Discov. 2019 May;18(5):339-357.
REF 4 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
REF 5 N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thioureas as potent vanilloid receptor antagonistic ligands. Bioorg Med Chem Lett. 2004 Apr 5;14(7):1693-6.
REF 6 Modulation of the transient receptor potential vanilloid channel TRPV4 by 4alpha-phorbol esters: a structure-activity study. J Med Chem. 2009 May 14;52(9):2933-9.
REF 7 Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels. Nature. 2003 Jul 24;424(6947):434-8.
REF 8 Bisandrographolide from Andrographis paniculata activates TRPV4 channels. J Biol Chem. 2006 Oct 6;281(40):29897-904.
REF 9 Chain-branched acyclic phenethylthiocarbamates as vanilloid receptor antagonists. Bioorg Med Chem Lett. 2003 May 5;13(9):1549-52.
REF 10 Impaired pressure sensation in mice lacking TRPV4. J Biol Chem. 2003 Jun 20;278(25):22664-8.
REF 11 N-((1S)-1-{[4-((2S)-2-{[(2,4-dichlorophenyl)sulfonyl]amino}-3-hydroxypropanoyl)-1-piperazinyl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide (GSK1016790A), a novel and potent transient receptor potential vanilloid 4 channel agonist induces urinary bladder contraction and hyperactivity: Part I. J Pharmacol Exp Ther. 2008 Aug;326(2):432-42.
REF 12 An orally active TRPV4 channel blocker prevents and resolves pulmonary edema induced by heart failure. Sci Transl Med. 2012 Nov 7;4(159):159ra148.
REF 13 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.
REF 14 Novel non-vanilloid VR1 antagonist of high analgesic effects and its structural requirement for VR1 antagonistic effects. Bioorg Med Chem Lett. 2003 Dec 15;13(24):4389-93.
REF 15 Identification and characterization of novel TRPV4 modulators. Biochem Biophys Res Commun. 2009 Nov 20;389(3):490-4.

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