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)",[1][2] a member of the vanilloid subfamily in the transient receptor potential (TRP) superfamily of ion channels.[3][4][5] 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.[1] and R. Strotmann et al.[2]
A number of TRPV4 agonists and antagonists have been identified since its discovery.[7] The discovery of unselective modulators (e.g. antagonist Ruthenium Red) was followed by the apparition of more potent (agonist 4aPDD)[8] or selective (antagonist RN-1734)[9] compounds, including some with bioavailability suitable for in vivo pharmacology studies such as agonist GSK1016790A[10] (with ~10 fold selectivity vs TRPV1), and antagonists HC-067047[11] (with ~5 fold selectivity vs hERG and ~10 fold selectivity vs TRPM8) and RN-9893[12] (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 neruons 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.[13][14][15][16][17]
↑Clapham DE, Julius D, Montell C, Schultz G (Dec 2005). "International Union of Pharmacology. XLIX. Nomenclature and structure-function relationships of transient receptor potential channels". Pharmacol. Rev. 57 (4): 427–50. doi:10.1124/pr.57.4.6. PMID16382100.
↑Harteneck C, Plant TD, Schultz G (April 2000). "From worm to man: three subfamilies of TRP channels". Trends Neurosci. 23 (4): 159–66. doi:10.1016/S0166-2236(99)01532-5. PMID10717675.
↑Watanabe H, Davis JB, Smart D, Jerman JC, Smith GD, Hayes P, Vriens J, Cairns W, Wissenbach U, Prenen J, Flockerzi V, Droogmans G, Benham CD, Nilius B (April 2002). "Activation of TRPV4 channels (hVRL-2/mTRP12) by phorbol derivatives". J. Biol. Chem. 277 (16): 13569–77. doi:10.1074/jbc.M200062200. PMID11827975.
↑Vincent F, Acevedo A, Nguyen MT, Dourado M, DeFalco J, Gustafson A, Spiro P, Emerling DE, Kelly MG, Duncton MA (November 2009). "Identification and characterization of novel TRPV4 modulators". Biochem. Biophys. Res. Commun. 389 (3): 490–4. doi:10.1016/j.bbrc.2009.09.007. PMID19737537.
↑Thorneloe KS, Sulpizio AC, Lin Z, Figueroa DJ, Clouse AK, McCafferty GP, Chendrimada TP, Lashinger ES, Gordon E, Evans L, Misajet BA, Demarini DJ, Nation JH, Casillas LN, Marquis RW, Votta BJ, Sheardown SA, Xu X, Brooks DP, Laping NJ, Westfall TD (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". J. Pharmacol. Exp. Ther. 326 (2): 432–42. doi:10.1124/jpet.108.139295. PMID18499743.
↑Wei ZL, Nguyen MT, O'Mahony DJ, Acevedo A, Zipfel S, Zhang Q, Liu L, Dourado M, Chi C, Yip V, DeFalco J, Gustafson A, Emerling DE, Kelly MG, Kincaid J, Vincent F, Duncton MA (2015). "Identification of orally-bioavailable antagonists of the TRPV4 ion-channel". Bioorg. Med. Chem. Lett. 25 (18): 4011–5. doi:10.1016/j.bmcl.2015.06.098. PMID26235950.
↑Qu Q, Xuan W, Fan GH (2015). "Roles of resolvins in the resolution of acute inflammation". Cell Biology International. 39 (1): 3–22. doi:10.1002/cbin.10345. PMID25052386.
↑Suzuki M, Hirao A, Mizuno A (December 2003). "Microtubule-associated [corrected] protein 7 increases the membrane expression of transient receptor potential vanilloid 4 (TRPV4)". J. Biol. Chem. 278 (51): 51448–53. doi:10.1074/jbc.M308212200. PMID14517216.
↑Xu H, Zhao H, Tian W, Yoshida K, Roullet JB, Cohen DM (Mar 2003). "Regulation of a transient receptor potential (TRP) channel by tyrosine phosphorylation. SRC family kinase-dependent tyrosine phosphorylation of TRPV4 on TYR-253 mediates its response to hypotonic stress". J. Biol. Chem. 278 (13): 11520–7. doi:10.1074/jbc.M211061200. PMID12538589.