TRPV4 explained

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 channel, member 4 (OTRPC4)", a member of the vanilloid subfamily in the transient receptor potential (TRP) superfamily of ion channels.[1] [2] [3] 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.[4] and R. Strotmann et al.[5]

Clinical significance

Channelopathy mutations 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, Familial digital arthropathy-brachydactyly (FDAB),[6] scapuloperoneal spinal muscular atrophy, and subtype 2C of Charcot–Marie–Tooth disease.

Pharmacology

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 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.[13] [14] [15] [16] [17]

Interactions

TRPV4 has been shown to interact with MAP7[18] and LYN.[19]

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.[20] 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.

See also

External links

Notes and References

  1. Clapham DE, Julius D, Montell C, Schultz G . International Union of Pharmacology. XLIX. Nomenclature and structure-function relationships of transient receptor potential channels . Pharmacological Reviews . 57 . 4 . 427–450 . December 2005 . 16382100 . 10.1124/pr.57.4.6 . 17936350 .
  2. Harteneck C, Plant TD, Schultz G . From worm to man: three subfamilies of TRP channels . Trends in Neurosciences . 23 . 4 . 159–166 . April 2000 . 10717675 . 10.1016/S0166-2236(99)01532-5 . 41074873 .
  3. Book: Plant TD, Strotmann R . TRPV4 . Transient Receptor Potential (TRP) Channels. Handbook of Experimental Pharmacology . 179 . . 189–205 . 2007 . 17217058 . 10.1007/978-3-540-34891-7_11 . 978-3-540-34889-4 .
  4. Liedtke W, Choe Y, Martí-Renom MA, Bell AM, Denis CS, Sali A, Hudspeth AJ, Friedman JM, Heller S . 6 . Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor . Cell . 103 . 3 . 525–535 . October 2000 . 11081638 . 2211528 . 10.1016/S0092-8674(00)00143-4 .
  5. Strotmann R, Harteneck C, Nunnenmacher K, Schultz G, Plant TD . OTRPC4, a nonselective cation channel that confers sensitivity to extracellular osmolarity . Nature Cell Biology . 2 . 10 . 695–702 . October 2000 . 11025659 . 10.1038/35036318 . 21148080 .
  6. Lamandé SR, Yuan Y, Gresshoff IL, Rowley L, Belluoccio D, Kaluarachchi K, Little CB, Botzenhart E, Zerres K, Amor DJ, Cole WG, Savarirayan R, McIntyre P, Bateman JF . 6 . Mutations in TRPV4 cause an inherited arthropathy of hands and feet . Nature Genetics . 43 . 11 . 1142–1146 . October 2011 . 21964574 . 10.1038/ng.945 . 27430401 .
  7. Vincent F, Duncton MA . TRPV4 agonists and antagonists . Current Topics in Medicinal Chemistry . 11 . 17 . 2216–2226 . 2011 . 21671873 . 10.2174/156802611796904861 .
  8. 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 . 6 . Activation of TRPV4 channels (hVRL-2/mTRP12) by phorbol derivatives . The Journal of Biological Chemistry . 277 . 16 . 13569–13577 . April 2002 . 11827975 . 10.1074/jbc.M200062200 . free .
  9. Vincent F, Acevedo A, Nguyen MT, Dourado M, DeFalco J, Gustafson A, Spiro P, Emerling DE, Kelly MG, Duncton MA . 6 . Identification and characterization of novel TRPV4 modulators . Biochemical and Biophysical Research Communications . 389 . 3 . 490–494 . November 2009 . 19737537 . 10.1016/j.bbrc.2009.09.007 .
  10. 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 . 6 . N-((1S)-1--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 . August 2008 . 18499743 . 10.1124/jpet.108.139295 . 517735 .
  11. 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 . 6 . Inhibition of the cation channel TRPV4 improves bladder function in mice and rats with cyclophosphamide-induced cystitis . Proceedings of the National Academy of Sciences of the United States of America . 107 . 44 . 19084–19089 . November 2010 . 20956320 . 2973867 . 10.1073/pnas.1005333107 . free . 2010PNAS..10719084E .
  12. 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 . 6 . Identification of orally-bioavailable antagonists of the TRPV4 ion-channel . Bioorganic & Medicinal Chemistry Letters . 25 . 18 . 4011–4015 . September 2015 . 26235950 . 10.1016/j.bmcl.2015.06.098 .
  13. Qu Q, Xuan W, Fan GH . Roles of resolvins in the resolution of acute inflammation . Cell Biology International . 39 . 1 . 3–22 . January 2015 . 25052386 . 10.1002/cbin.10345 . 10160642 .
  14. Serhan CN, Chiang N, Dalli J, Levy BD . Lipid mediators in the resolution of inflammation . Cold Spring Harbor Perspectives in Biology . 7 . 2 . a016311 . October 2014 . 25359497 . 4315926 . 10.1101/cshperspect.a016311 .
  15. Lim JY, Park CK, Hwang SW . Biological Roles of Resolvins and Related Substances in the Resolution of Pain . BioMed Research International . 2015 . 830930 . 2015 . 26339646 . 4538417 . 10.1155/2015/830930 . free .
  16. Ji RR, Xu ZZ, Strichartz G, Serhan CN . Emerging roles of resolvins in the resolution of inflammation and pain . Trends in Neurosciences . 34 . 11 . 599–609 . November 2011 . 21963090 . 3200462 . 10.1016/j.tins.2011.08.005 .
  17. Serhan CN, Chiang N, Dalli J . The resolution code of acute inflammation: Novel pro-resolving lipid mediators in resolution . Seminars in Immunology . 27 . 3 . 200–215 . May 2015 . 25857211 . 4515371 . 10.1016/j.smim.2015.03.004 .
  18. Suzuki M, Hirao A, Mizuno A . Microtubule-associated [corrected] protein 7 increases the membrane expression of transient receptor potential vanilloid 4 (TRPV4) . The Journal of Biological Chemistry . 278 . 51 . 51448–51453 . December 2003 . 14517216 . 10.1074/jbc.M308212200 . free .
  19. Xu H, Zhao H, Tian W, Yoshida K, Roullet JB, Cohen DM . 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 . The Journal of Biological Chemistry . 278 . 13 . 11520–11527 . March 2003 . 12538589 . 10.1074/jbc.M211061200 . free .
  20. Yatsu R, Miyagawa S, Kohno S, Saito S, Lowers RH, Ogino Y, Fukuta N, Katsu Y, Ohta Y, Tominaga M, Guillette LJ, Iguchi T . TRPV4 associates environmental temperature and sex determination in the American alligator . Sci Rep . 2015 . 5 . 18581 . 10.1038/srep18581 . 26677944 . 4683465 . free . 2015NatSR...518581Y .

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