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Gene Review

TRPV4  -  transient receptor potential cation...

Homo sapiens

Synonyms: CMT2C, HMSN2C, OTRPC4, Osm-9-like TRP channel 4, SMAL, ...
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Disease relevance of TRPV4

  • Swelling-activated Ca2+ entry via TRPV4 channel is defective in cystic fibrosis airway epithelia [1].
  • Because TRPV4 and WNK kinases are coexpressed in the distal nephron in vivo and because there is a tendency toward hypercalcemia in TRPV4-/- mice, we speculate that this pathway may impact systemic Ca2+ balance [2].
  • We also hypothesize that closing of some TRP channels (TRPV3 and/or TRPV4) by lowering temperature may be partly responsible for the neuroprotective effect of hypothermia [3].
  • Collectively, these findings implicate TRPV4 in disruption of the alveolar septal barrier and suggest its participation in the pathogenesis of acute lung injury [4].
  • Light and electron microscopy of rat and mouse lung revealed that TRPV4 agonists preferentially produced blebs or breaks in the endothelial and epithelial layers of the alveolar septal wall, whereas thapsigargin disrupted interendothelial junctions in extraalveolar vessels [4].

High impact information on TRPV4

  • TRPV4 is a widely expressed member of the transient receptor potential (TRP) family that facilitates Ca(2+) entry into nonexcitable cells [5].
  • Here, we show that ubiquitination represents an important mechanism to control the presence of TRPV4 at the plasma membrane [5].
  • Therefore, TRPV4 emerges as a candidate to participate in the coupling of fluid viscosity changes to the generation of the Ca(2+) signal required for the autoregulation of CBF [6].
  • Hypotonic reduction of AQP5 was observed only in the presence of TRPV4 and was blocked by ruthenium red [7].
  • TRPV4 is a Ca(2+)- and Mg(2+)-permeable cation channel within the vanilloid receptor subgroup of the transient receptor potential (TRP) family, and it has been implicated in Ca(2+)-dependent signal transduction in several tissues, including brain and vascular endothelium [8].

Biological context of TRPV4

  • TRPV4 is a Ca2+ entry channel that is activated by an increase in cell volume, which might be involved in mechano-sensing, by an increase in temperature, and perhaps by ligand-activation [9].
  • Ca2+-dependent potentiation of the nonselective cation channel TRPV4 is mediated by a C-terminal calmodulin binding site [10].
  • A similar shift was also observable when we blocked dynamin-mediated endocytotic processes, suggesting that PACSIN 3 specifically affects the endocytosis of TRPV4, thereby modulating the subcellular localization of the ion channel [11].
  • In a Caenorhabditis elegans TRPV mutant transgenic for mammalian TRPV4, the mammalian transgene was directing the osmotic and mechanical avoidance response in the context of the ASH 'nociceptive' neurone [12].
  • Using a combination of in silico analysis of expressed sequence tag (EST) databases and conventional molecular cloning, we have isolated a novel vanilloid-like receptor, which we call VRL-2, from human kidney [13].

Anatomical context of TRPV4


Associations of TRPV4 with chemical compounds

  • It will be shown that lipid messengers related to arachidonic acid are endogenous TRPV4 activators [18].
  • Five of them can alternatively be activated by nonthermal stimuli such as capsaicin [transient receptor potential vanilloid 1 (TRPV1)] or hypo-osmolarity (TRPV2 and TRPV4) [19].
  • Application of the TRPV4 synthetic ligand 4alpha-phorbol 12,13-didecanoate increased cationic currents, intracellular Ca(2+), and the CBF in the absence of a viscous load [6].
  • Bisandrographolide from Andrographis paniculata Activates TRPV4 Channels [20].
  • We identify two aspartate residues, Asp(672) and Asp(682), as important determinants of the Ca(2+) sensitivity of the TRPV4 pore [21].
  • Because the SFK-mediated phosphorylation of the N-terminal tyrosine occurred before TRPV4 activation, tyrosine phosphorylation appears to sensitize rather than activate this channel [22].

Physical interactions of TRPV4

  • A detailed analysis of the underlying mechanisms revealed that OS-9 preferably binds TRPV4 monomers and other ER-localized, immature variants of TRPV4 and attenuates their polyubiquitination [23].

Regulatory relationships of TRPV4


Other interactions of TRPV4

  • Both TRPV3 and TRPV4 are expressed in 308 cells [14].
  • We conclude that TRPV1 and TRPV4 channels provide Ca(2+) entry pathways in HepG2 cells [25].
  • Data from the study of mice in which TRPV2, TRPV3 or TRPV4 have been deleted are also eagerly awaited [16].
  • Among the two other TRP subfamilies, TRPMV and TRPM, at least TRPV4 and TRPM4 are EC channels [9].
  • Consistent with this, endogenous TRPV4 was detected in cells and in the apical region of acini along AQP5 [26].

Analytical, diagnostic and therapeutic context of TRPV4


  1. Swelling-activated Ca2+ entry via TRPV4 channel is defective in cystic fibrosis airway epithelia. Arniges, M., Vázquez, E., Fernández-Fernández, J.M., Valverde, M.A. J. Biol. Chem. (2004) [Pubmed]
  2. WNK kinases influence TRPV4 channel function and localization. Fu, Y., Subramanya, A., Rozansky, D., Cohen, D.M. Am. J. Physiol. Renal Physiol. (2006) [Pubmed]
  3. Involvement of TRP-like channels in the acute ischemic response of hippocampal CA1 neurons in brain slices. Lipski, J., Park, T.I., Li, D., Lee, S.C., Trevarton, A.J., Chung, K.K., Freestone, P.S., Bai, J.Z. Brain Res. (2006) [Pubmed]
  4. Transient receptor potential vanilloid 4-mediated disruption of the alveolar septal barrier: a novel mechanism of acute lung injury. Alvarez, D.F., King, J.A., Weber, D., Addison, E., Liedtke, W., Townsley, M.I. Circ. Res. (2006) [Pubmed]
  5. The HECT ubiquitin ligase AIP4 regulates the cell surface expression of select TRP channels. Wegierski, T., Hill, K., Schaefer, M., Walz, G. EMBO J. (2006) [Pubmed]
  6. TRPV4 channel is involved in the coupling of fluid viscosity changes to epithelial ciliary activity. Andrade, Y.N., Fernandes, J., Vázquez, E., Fernández-Fernández, J.M., Arniges, M., Sánchez, T.M., Villalón, M., Valverde, M.A. J. Cell Biol. (2005) [Pubmed]
  7. Transient receptor potential vanilloid 4 regulates aquaporin-5 abundance under hypotonic conditions. Sidhaye, V.K., Güler, A.D., Schweitzer, K.S., D'Alessio, F., Caterina, M.J., King, L.S. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  8. Cell swelling, heat, and chemical agonists use distinct pathways for the activation of the cation channel TRPV4. Vriens, J., Watanabe, H., Janssens, A., Droogmans, G., Voets, T., Nilius, B. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  9. Transient receptor potential channels in endothelium: solving the calcium entry puzzle? Nilius, B., Droogmans, G., Wondergem, R. Endothelium (2003) [Pubmed]
  10. Ca2+-dependent potentiation of the nonselective cation channel TRPV4 is mediated by a C-terminal calmodulin binding site. Strotmann, R., Schultz, G., Plant, T.D. J. Biol. Chem. (2003) [Pubmed]
  11. PACSINs bind to the TRPV4 cation channel. PACSIN 3 modulates the subcellular localization of TRPV4. Cuajungco, M.P., Grimm, C., Oshima, K., D'hoedt, D., Nilius, B., Mensenkamp, A.R., Bindels, R.J., Plomann, M., Heller, S. J. Biol. Chem. (2006) [Pubmed]
  12. TRPV4 plays an evolutionary conserved role in the transduction of osmotic and mechanical stimuli in live animals. Liedtke, W. J. Physiol. (Lond.) (2005) [Pubmed]
  13. Identification and characterization of a novel human vanilloid receptor-like protein, VRL-2. Delany, N.S., Hurle, M., Facer, P., Alnadaf, T., Plumpton, C., Kinghorn, I., See, C.G., Costigan, M., Anand, P., Woolf, C.J., Crowther, D., Sanseau, P., Tate, S.N. Physiol. Genomics (2001) [Pubmed]
  14. Warm temperatures activate TRPV4 in mouse 308 keratinocytes. Chung, M.K., Lee, H., Caterina, M.J. J. Biol. Chem. (2003) [Pubmed]
  15. Functional TRPV4 channels are expressed in human airway smooth muscle cells. Jia, Y., Wang, X., Varty, L., Rizzo, C.A., Yang, R., Correll, C.C., Phelps, P.T., Egan, R.W., Hey, J.A. Am. J. Physiol. Lung Cell Mol. Physiol. (2004) [Pubmed]
  16. TRPV channels as temperature sensors. Benham, C.D., Gunthorpe, M.J., Davis, J.B. Cell Calcium (2003) [Pubmed]
  17. Heat-evoked activation of the ion channel, TRPV4. Güler, A.D., Lee, H., Iida, T., Shimizu, I., Tominaga, M., Caterina, M. J. Neurosci. (2002) [Pubmed]
  18. Diversity of TRP channel activation. Nilius, B., Voets, T. Novartis Found. Symp. (2004) [Pubmed]
  19. 2-aminoethoxydiphenyl borate activates and sensitizes the heat-gated ion channel TRPV3. Chung, M.K., Lee, H., Mizuno, A., Suzuki, M., Caterina, M.J. J. Neurosci. (2004) [Pubmed]
  20. Bisandrographolide from Andrographis paniculata Activates TRPV4 Channels. Smith, P.L., Maloney, K.N., Pothen, R.G., Clardy, J., Clapham, D.E. J. Biol. Chem. (2006) [Pubmed]
  21. Molecular determinants of permeation through the cation channel TRPV4. Voets, T., Prenen, J., Vriens, J., Watanabe, H., Janssens, A., Wissenbach, U., Bödding, M., Droogmans, G., Nilius, B. J. Biol. Chem. (2002) [Pubmed]
  22. Tyrosine phosphorylation modulates the activity of TRPV4 in response to defined stimuli. Wegierski, T., Lewandrowski, U., Müller, B., Sickmann, A., Walz, G. J. Biol. Chem. (2009) [Pubmed]
  23. OS-9 regulates the transit and polyubiquitination of TRPV4 in the endoplasmic reticulum. Wang, Y., Fu, X., Gaiser, S., Köttgen, M., Kramer-Zucker, A., Walz, G., Wegierski, T. J. Biol. Chem. (2007) [Pubmed]
  24. Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels. Watanabe, H., Vriens, J., Prenen, J., Droogmans, G., Voets, T., Nilius, B. Nature (2003) [Pubmed]
  25. TRPV channels and modulation by hepatocyte growth factor/scatter factor in human hepatoblastoma (HepG2) cells. Vriens, J., Janssens, A., Prenen, J., Nilius, B., Wondergem, R. Cell Calcium (2004) [Pubmed]
  26. A role for AQP5 in activation of TRPV4 by hypotonicity: concerted involvement of AQP5 and TRPV4 in regulation of cell volume recovery. Liu, X., Bandyopadhyay, B., Nakamoto, T., Singh, B., Liedtke, W., Melvin, J.E., Ambudkar, I. J. Biol. Chem. (2006) [Pubmed]
  27. 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. Xu, H., Zhao, H., Tian, W., Yoshida, K., Roullet, J.B., Cohen, D.M. J. Biol. Chem. (2003) [Pubmed]
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