View source for TRPV4

{{Infobox_gene}}
'''Transient receptor potential cation channel subfamily V member 4''' is an ion channel protein that in humans is encoded by the ''TRPV4'' [[gene]].

The ''TRPV4'' gene encodes TRPV4, initially named "vanilloid-receptor related osmotically activated channel" (VR-OAC) and "OSM9-like [[transient receptor potential]] [[ion channel|channel]], member 4 (OTRPC4)",<ref name="pmid11081638"/><ref name="pmid11025659"/> a member of the vanilloid subfamily in the [[transient receptor potential]] (TRP) superfamily of [[ion channel]]s.<ref name="pmid16382100">{{cite journal | vauthors = Clapham DE, Julius D, Montell C, Schultz G | title = International Union of Pharmacology. XLIX. Nomenclature and structure-function relationships of transient receptor potential channels | journal = Pharmacol. Rev. | volume = 57 | issue = 4 | pages = 427–50  | date = Dec 2005 | pmid = 16382100 | pmc =  | doi = 10.1124/pr.57.4.6 }}</ref><ref name="pmid10717675">{{cite journal | vauthors = Harteneck C, Plant TD, Schultz G | title = From worm to man: three subfamilies of TRP channels | journal = Trends Neurosci. | volume = 23 | issue = 4 | pages = 159–66  | date = April 2000 | pmid = 10717675 | doi = 10.1016/S0166-2236(99)01532-5 }}</ref><ref name="pmid17217058">{{cite journal | vauthors = Plant TD, Strotmann R | title = TRPV4 | journal = Handb Exp Pharmacol | volume = 179 | issue = 179 | pages = 189–205 | year = 2007 | pmid = 17217058 | doi = 10.1007/978-3-540-34891-7_11 }}</ref> The encoded protein is a Ca<sup>2+</sup>-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.<ref name="pmid11081638">{{cite journal | vauthors = Liedtke W, Choe Y, Martí-Renom MA, Bell AM, Denis CS, Sali A, Hudspeth AJ, Friedman JM, Heller S | title = Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor | journal = Cell | volume = 103 | issue = 3 | pages = 525–35  | date = October 2000 | pmid = 11081638 | pmc = 2211528 | doi = 10.1016/S0092-8674(00)00143-4 }}</ref> and R. Strotmann et al.<ref name="pmid11025659">{{cite journal | vauthors = Strotmann R, Harteneck C, Nunnenmacher K, Schultz G, Plant TD | title = OTRPC4, a nonselective cation channel that confers sensitivity to extracellular osmolarity | journal = Nat. Cell Biol. | volume = 2 | issue = 10 | pages = 695–702  | date = October 2000 | pmid = 11025659 | doi = 10.1038/35036318 }}</ref>

== Clinical significance ==

Channelopathy [[mutation]]s in the ''TRPV4'' gene lead to skeletal dysplasias, premature osteoarthritis, and neurological motor function disorders and are associated with a range of disorders, including [[brachyolmia]] type 3, [[congenital distal spinal muscular atrophy]], [[scapuloperoneal spinal muscular atrophy]], and subtype 2C of [[Charcot–Marie–Tooth disease]].<ref>{{OMIM|605427}}</ref>

== Pharmacology ==

A number of TRPV4 agonists and antagonists have been identified since its discovery.<ref>{{cite journal | vauthors = Vincent F, Duncton MA | title = TRPV4 agonists and antagonists | journal = Curr Top Med Chem | volume = 11 | issue = 17 | pages = 2216–26 | year = 2011 | pmid = 21671873 | doi =  10.2174/156802611796904861}}</ref> The discovery of unselective modulators (e.g. antagonist Ruthenium Red) was followed by the apparition of more potent (agonist 4aPDD)<ref>{{cite journal | vauthors = 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 | title = Activation of TRPV4 channels (hVRL-2/mTRP12) by phorbol derivatives | journal = J. Biol. Chem. | volume = 277 | issue = 16 | pages = 13569–77  | date = April 2002 | pmid = 11827975 | doi = 10.1074/jbc.M200062200 }}</ref> or selective (antagonist RN-1734)<ref>{{cite journal | vauthors = Vincent F, Acevedo A, Nguyen MT, Dourado M, DeFalco J, Gustafson A, Spiro P, Emerling DE, Kelly MG, Duncton MA | title = Identification and characterization of novel TRPV4 modulators | journal = Biochem. Biophys. Res. Commun. | volume = 389 | issue = 3 | pages = 490–4  | date = November 2009 | pmid = 19737537 | doi = 10.1016/j.bbrc.2009.09.007 }}</ref> compounds, including some with bioavailability suitable for in vivo pharmacology studies such as agonist GSK1016790A<ref>{{cite journal | vauthors = 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 | title = N-((1S)-1-<nowiki/>{[4-((2S)-2-<nowiki/>{[(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 | journal = J. Pharmacol. Exp. Ther. | volume = 326 | issue = 2 | pages = 432–42 | date = August 2008 | pmid = 18499743 | doi = 10.1124/jpet.108.139295 }}</ref> (with ~10 fold selectivity vs TRPV1), and antagonists HC-067047<ref>{{cite journal | vauthors = Everaerts W, Zhen X, Ghosh D, Vriens J, Gevaert T, Gilbert JP, Hayward NJ, McNamara CR, Xue F, Moran MM, Strassmaier T, Uykal E, Owsianik G, Vennekens R, De Ridder D, Nilius B, Fanger CM, Voets T | title = Inhibition of the cation channel TRPV4 improves bladder function in mice and rats with cyclophosphamide-induced cystitis | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 107 | issue = 44 | pages = 19084–9  | date = November 2010 | pmid = 20956320 | pmc = 2973867 | doi = 10.1073/pnas.1005333107 }}</ref> (with ~5 fold selectivity vs hERG and ~10 fold selectivity vs TRPM8) and RN-9893<ref>{{cite journal | vauthors = 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 | title = Identification of orally-bioavailable antagonists of the TRPV4 ion-channel | journal = Bioorg. Med. Chem. Lett. | volume = 25 | issue = 18 | pages = 4011–5 | date = 2015 | pmid=26235950 | doi=10.1016/j.bmcl.2015.06.098}}</ref> (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 [[astrocyte]]s. [[CMKLR1]], [[GPR32]], [[FPR2]], and [[NMDA receptor]]s have been proposed to be the receptors through which a SPM may operate to [[down-regulate]] TRPs and thereby pain perception.<ref name="pmid25052386">{{cite journal | vauthors = Qu Q, Xuan W, Fan GH | title = Roles of resolvins in the resolution of acute inflammation | journal = Cell Biology International | volume = 39 | issue = 1 | pages = 3–22 | year = 2015 | pmid = 25052386 | doi = 10.1002/cbin.10345 | url = }}</ref><ref name="pmid25359497">{{cite journal | vauthors = Serhan CN, Chiang N, Dalli J, Levy BD | title = Lipid mediators in the resolution of inflammation | journal = Cold Spring Harbor Perspectives in Biology | volume = 7 | issue = 2 | pages = a016311 | year = 2015 | pmid = 25359497 | doi = 10.1101/cshperspect.a016311 | pmc=4315926}}</ref><ref name="pmid26339646">{{cite journal | vauthors = Lim JY, Park CK, Hwang SW | title = Biological Roles of Resolvins and Related Substances in the Resolution of Pain | journal = BioMed Research International | volume = 2015 | issue = | pages = 830930 | year = 2015 | pmid = 26339646 | pmc = 4538417 | doi = 10.1155/2015/830930 | url = }}</ref><ref name="pmid21963090">{{cite journal | vauthors = Ji RR, Xu ZZ, Strichartz G, Serhan CN | title = Emerging roles of resolvins in the resolution of inflammation and pain | journal = Trends in Neurosciences | volume = 34 | issue = 11 | pages = 599–609 | year = 2011 | pmid = 21963090 | pmc = 3200462 | doi = 10.1016/j.tins.2011.08.005 | url = }}</ref><ref name="pmid25857211">{{cite journal | vauthors = Serhan CN, Chiang N, Dalli J | title = The resolution code of acute inflammation: Novel pro-resolving lipid mediators in resolution | journal = Seminars in Immunology | volume = 27 | issue = 3 | pages = 200–15 | year = 2015 | pmid = 25857211 | pmc = 4515371 | doi = 10.1016/j.smim.2015.03.004 | url = }}</ref>

== Interactions ==

TRPV4 has been shown to [[Protein-protein interaction|interact]] with [[MAP7]]<ref name="pmid14517216">{{cite journal | vauthors = Suzuki M, Hirao A, Mizuno A | title = Microtubule-associated [corrected] protein 7 increases the membrane expression of transient receptor potential vanilloid 4 (TRPV4) | journal = J. Biol. Chem. | volume = 278 | issue = 51 | pages = 51448–53  | date = December 2003 | pmid = 14517216 | doi = 10.1074/jbc.M308212200 }}</ref> and [[LYN]].<ref name=pmid12538589>{{cite journal | vauthors = Xu H, Zhao H, Tian W, Yoshida K, Roullet JB, Cohen DM | title = 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 | journal = J. Biol. Chem. | volume = 278 | issue = 13 | pages = 11520–7  | date = Mar 2003 | pmid = 12538589 | doi = 10.1074/jbc.M211061200 }}</ref>

== See also ==
* [[TRPV]]

== References ==
{{Reflist|30em}}

== External links ==
* [https://www.ncbi.nlm.nih.gov/books/NBK1285/  GeneReviews/NCBI/NIH/UW entry on Charcot-Marie-Tooth Neuropathy Type 2]
* {{MeshName|TRPV4+protein,+human}}

{{NLM content}}
{{Ion channels|g4}}
{{Transient receptor potential channel modulators}}

[[Category:Ion channels]]