Transient receptor potential cation channel subfamily V member 4 is an ion channel protein that in humans is encoded by the TRPV4gene.
The TRPV4 gene encodes TRPV4, initially named "vanilloid-receptor related osmotically activated channel" (VR-OAC) and "OSM9-like transient receptor potentialchannel, member 4 (OTRPC4)",[5][6] a member of the vanilloid subfamily in the transient receptor potential (TRP) superfamily of ion channels.[7][8][9] The encoded protein is a Ca2+-permeable, nonselective cation channel that has been found involved in multiple physiologic functions, dysfunctions and also disease. It functions in the regulation of systemic osmotic pressure by the brain, in vascular function, in liver, intestinal, renal and bladder function, in skin barrier function and response of the skin to ultraviolet-B radiation, in growth and structural integrity of the skeleton, in function of joints, in airway- and lung function, in retinal and inner ear function, and in pain. The channel is activated by osmotic, mechanical and chemical cues. It also responds to thermal changes (warmth). Channel activation can be sensitized by inflammation and injury.
The TRPV4 gene has been co-discovered by W. Liedtke et al.[5] and R. Strotmann et al.[6]
A number of TRPV4 agonists and antagonists have been identified since its discovery.[12] The discovery of unselective modulators (e.g. antagonist ruthenium red) was followed by the apparition of more potent (agonist 4aPDD)[13] or selective (antagonist RN-1734)[14] compounds, including some with bioavailability suitable for in vivo pharmacology studies such as agonist GSK1016790A[15] (with ~10 fold selectivity vs TRPV1), and antagonists HC-067047[16] (with ~5 fold selectivity vs hERG and ~10 fold selectivity vs TRPM8) and RN-9893[17] (with ~50 fold selectivity vs TRPM8 and ~10 fold selectivity vs M1).
Resolvin D1 (RvD1), a metabolite of the omega 3 fatty acid, docosahexaenoic acid, is a member of the specialized proresolving mediators (SPMs) class of metabolites that function to resolve diverse inflammatory reactions and diseases in animal models and, it is proposed, humans. This SPM also dampens pain perception arising from various inflammation-based causes in animal models. The mechanism behind this pain-dampening effect involves the inhibition of TRPV4, probably (in at least certain cases) by an indirect effect wherein it activates another receptor located on neurons or nearby microglia or astrocytes. CMKLR1, GPR32, FPR2, and NMDA receptors have been proposed to be the receptors through which a SPM may operate to down-regulate TRPs and thereby pain perception.[18][19][20][21][22]
Implication in Temperature-Dependent Sex Determination in Reptiles
TRPV4 has been proposed to be the thermal sensor in gonads of Alligator mississipiensis, a species with temperature-dependent sex determination.[25] However the data were over interpreted and TRPV4 is probably not involved in temperature-dependent sex determination due to large overlap of expression at male producing temperature and female producing temperature for example.
^Clapham DE, Julius D, Montell C, Schultz G (December 2005). "International Union of Pharmacology. XLIX. Nomenclature and structure-function relationships of transient receptor potential channels". Pharmacological Reviews. 57 (4): 427–450. doi:10.1124/pr.57.4.6. PMID16382100. S2CID17936350.
^Lamandé SR, Yuan Y, Gresshoff IL, Rowley L, Belluoccio D, Kaluarachchi K, et al. (October 2011). "Mutations in TRPV4 cause an inherited arthropathy of hands and feet". Nature Genetics. 43 (11): 1142–1146. doi:10.1038/ng.945. PMID21964574. S2CID27430401.
^Vincent F, Duncton MA (2011). "TRPV4 agonists and antagonists". Current Topics in Medicinal Chemistry. 11 (17): 2216–2226. doi:10.2174/156802611796904861. PMID21671873.
^Vincent F, Acevedo A, Nguyen MT, Dourado M, DeFalco J, Gustafson A, et al. (November 2009). "Identification and characterization of novel TRPV4 modulators". Biochemical and Biophysical Research Communications. 389 (3): 490–494. doi:10.1016/j.bbrc.2009.09.007. PMID19737537.
^Thorneloe KS, Sulpizio AC, Lin Z, Figueroa DJ, Clouse AK, McCafferty GP, et al. (August 2008). "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". The Journal of Pharmacology and Experimental Therapeutics. 326 (2): 432–442. doi:10.1124/jpet.108.139295. PMID18499743. S2CID517735.
^Wei ZL, Nguyen MT, O'Mahony DJ, Acevedo A, Zipfel S, Zhang Q, et al. (September 2015). "Identification of orally-bioavailable antagonists of the TRPV4 ion-channel". Bioorganic & Medicinal Chemistry Letters. 25 (18): 4011–4015. doi:10.1016/j.bmcl.2015.06.098. PMID26235950.
^Qu Q, Xuan W, Fan GH (January 2015). "Roles of resolvins in the resolution of acute inflammation". Cell Biology International. 39 (1): 3–22. doi:10.1002/cbin.10345. PMID25052386. S2CID10160642.
