Abstract
TRPV4 is a non-selective cation channel subunit expressed in a wide variety of tissues. TRP channels are formed by a tetrameric complex of channel subunits. The available evidence suggests that TRPV4 cannot form heteromultimers with other TRPV isoforms, and that TRPV4-containing channels are homotetramers. These channels have a characteristic outwardly rectifying current-voltage relation, and are 5–10 times more permeable for Ca2+ than for Na+. TRPV4 can be activated by a wide range of stimuli including physical (cell swelling, heat, mechanical stimulation) and chemical stimuli (endocannabinoids, arachidonic acid, and, surprisingly, 4α-phorbol esters). Activation by swelling and endocannabinoids involves cytochrome P450 epoxygenase-dependent arachidonic acid metabolism to the epoxyeicosatrienoic acids (EETs). Heat and 4α-phorbol esters also seem to share a common mechanism of activation, but the endogenous messenger involved in the response to heat has not yet been identified. Ca2+ acting from the intracellular side can have both potentiating and inhibitory effects on channel activity and is involved in channel activation and inactivation. Given its wide expression and the variety of activatory stimuli, TRPV4 is likely to play a number of physiological roles. Studies with TRPV4 -/- mice suggest a role for the channel in the regulation of body osmolarity, mechanosensation, temperature sensing, vascular regulation and, possibly, hearing.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
References
Alessandri-Haber N, Yeh JJ, Boyd AE, Parada CA, Chen X, Reichling DB, Levine JD (2003) Hypotonicity induces TRPV4-mediated nociception in rat. Neuron 39:497–511
Alessandri-Haber N, Dina OA, Yeh JJ, Parada CA, Reichling DB, Levine JD (2004) Transient receptor potential vanilloid 4 is essential in chemotherapy-induced neuropathic pain in the rat. J Neurosci 24:4444–4452
Andrade YN, Fernandes J, Vazquez E, Fernandez-Fernandez JM, Arniges M, Sanchez TM, Villalon M, Valverde MA (2005) TRPV4 channel is involved in the coupling of fluid viscosity changes to epithelial ciliary activity. J Cell Biol 168:869–874
Arniges M, Fernandez-Fernandez JM, Albrecht N, Schaefer M, Valverde MA (2006) Human TRPV4 channel splice variants revealed a key role of ankyrin domains in multimerization and trafficking. J Biol Chem 281:1580–1586
Becker D, Blase C, Bereiter-Hahn J, Jendrach M (2005) TRPV4 exhibits a functional role in cell-volume regulation. J Cell Sci 118:2435–2440
Bhave G, Hu HJ, Glauner KS, Zhu W, Wang H, Brasier DJ, Oxford GS, Gereau RW (2003) Protein kinase C phosphorylation sensitizes but does not activate the capsaicin receptor transient receptor potential vanilloid 1 (TRPV1). Proc Natl Acad Sci USA 100:12480–12485
Chung MK, Lee H, Caterina MJ (2003) Warm temperatures activate TRPV4 in mouse 308 keratinocytes. J Biol Chem 278:32037–32046
Chung MK, Lee H, Mizuno A, Suzuki M, Caterina MJ (2004) TRPV3 and TRPV4 mediate warmth-evoked currents in primary mouse keratinocytes. J Biol Chem 279:21569–21575
Colbert HA, Smith TL, Bargmann CI (1997) Osm-9, a novel protein with structural similarity to channels, is required for olfaction, mechanosensation and olfactory adaptation in Caenorhabditis elegans. J Neurosci 17:8259–8269
Corey DP, Garcia-Anoveros J, Holt JR, Kwan KY, Lin SY, Vollrath MA, Amalfitano A, Cheung EL, Derfler BH, Duggan A, Geleoc GS, Gray PA, Hoffman MP, Rehm HL, Tamasauskas D, Zhang DS (2004) TRPA1 is a candidate for the mechanosensitive transduction channel of vertebrate hair cells. Nature 432:723–730
Delany NS, Hurle M, Facer P, Alnadaf T, Plumpton C, Kinghorn I, See CG, Costigan M, Anand P, Woolf CJ, Crowther D, Sanseau P, Tate SN (2001) Identification and characterization of a novel human vanilloid receptor-like protein, VRL-2. Physiol Genomics 4:165–174
Earley S, Heppner TJ, Nelson MT, Brayden JE (2005) TRPV4 forms a novel Ca2+ signaling complex with ryanodine receptors and BKCa channels. Circ Res 97:1270–1279
Gao X, Wu L, O’Neil RG (2003) Temperature-modulated diversity of TRPV4 channel gating: activation by physical stresses and phorbol ester derivatives through protein kinase C-dependent and-independent pathways. J Biol Chem 278:27129–27137
Guatteo E, Chung KK, Bowala TK, Bernardi G, Mercuri NB, Lipski J (2005) Temperature sensitivity of dopaminergic neurons of the substantia nigra pars compacta: involvement of TRP channels. J Neurophysiol 94:3069–3080
Güler AD, Lee H, Iida T, Shimizu I, Tominaga M, Caterina M (2002) Heat-evoked activation of the ion channel, TRPV4. J Neurosci 22:6408–6414
Hellwig N, Albrecht N, Harteneck C, Schultz G, Schaefer M (2005) Homo-and heteromeric assembly of TRPV channel subunits. J Cell Sci 118:917–928
Hoffmann EK (2000) Intracellular signalling involved in volume regulatory decrease. Cell Physiol Biochem 10:273–288
Jia Y, Wang X, Varty L, Rizzo CA, Yang R, Correll CC, Phelps PT, Egan RW, Hey JA (2004) Functional TRPV4 channels are expressed in human airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 287:L272–278
Jordt SE, Julius D (2002) Molecular basis for species-specific sensitivity to“hot” chilipeppers. Cell 108:421–430
Jordt SE, Tominaga M, Julius D (2000) Acid potentiation of the capsaicin receptor determined by a key extracellular site. Proc Natl Acad Sci USA 97:8134–8139
Lambers TT, Weidema AF, Nilius B, Hoenderop JG, Bindels RJ (2004) Regulation of the mouse epithelial Ca2+ channel TRPV6 by the Ca2+-sensor calmodulin. J Biol Chem 279:28855–28861
Lee H, Iida T, Mizuno A, Suzuki M, Caterina MJ (2005) Altered thermal selection behavior in mice lacking transient receptor potential vanilloid 4. J Neurosci 25:1304–1310
Liedtke W, Friedman JM (2003) Abnormal osmotic regulation in trpv4-/- mice. Proc Natl Acad Sci USA 100:13698–13703
Liedtke W, Choe Y, Marti-Renom MA, Bell AM, Denis CS, Sali A, Hudspeth AJ, Friedman JM, Heller S (2000) Vanilloid receptor-related osmotically activated channel (VROAC), a candidate vertebrate osmoreceptor. Cell 103:525–535
Liedtke W, Tobin DM, Bargmann CI, Friedman JM (2003) Mammalian TRPV4 (VR-OAC) directs behavioral responses to osmotic and mechanical stimuli in Caenorhabditis elegans. Proc Natl Acad Sci USA 100Suppl 2:14531–14536
Mizuno A, Matsumoto N, Imai M, Suzuki M (2003) Impaired osmotic sensation in mice lacking TRPV4. Am J Physiol Cell Physiol 285:C96–101
Nagata K, Duggan A, Kumar G, Garcia-Anoveros J (2005) Nociceptor and hair cell transducer properties of TRPA1, a channel for pain and hearing. J Neurosci 25:4052–4061
Niemeyer BA, Bergs C, Wissenbach U, Flockerzi V, Trost C (2001) Competitive regulation of CaT-like-mediated Ca2+ entry by protein kinase C and calmodulin. Proc Natl Acad Sci USA 98:3600–3605
Nilius B, Prenen J, Wissenbach U, Bödding M, Droogmans G (2001) Differential activation of the volume-sensitive cation channel TRP12 (OTRPC4) and volume-regulated anion currents in HEK-293 cells. Pflügers Arch 443:227–233
Nilius B, Droogmans G, Wondergem R (2003) Transient receptor potential channels in endothelium: solving the calcium entry puzzle? Endothelium 10:5–15
O’Neil RG, Heller S (2005) The mechanosensitive nature of TRPV channels. Pflügers Arch 451:193–203
Strotmann R, Harteneck C, Nunnenmacher K, Schultz G, Plant TD (2000) OTRPC4, a nonselective cation channel that confers sensitivity to extracellular osmolarity. Nat Cell Biol 2:695–702
Strotmann R, Schultz G, Plant TD (2003) Ca2+-dependent potentiation of the nonselective cation channel TRPV4 is mediated by a C-terminal calmodulin binding site. J Biol Chem 278:26541–26549
Suzuki M, Mizuno A, Kodaira K, Imai M (2003) Impaired pressure sensation in mice lacking TRPV4. J Biol Chem 278:22664–22668
Tabuchi K, Suzuki M, Mizuno A, Hara A (2005) Hearing impairment in TRPV4 knockout mice. Neurosci Lett 382:304–308
Takumida M, Kubo N, Ohtani M, Suzuka Y, Anniko M (2005) Transient receptor potential channels in the inner ear: presence of transient receptor potential channel subfamily 1 and 4 in the guinea pig inner ear. Acta Otolaryngol 125:929–934
Tian W, Salanova M, Xu H, Lindsley JN, Oyama TT, Anderson S, Bachmann S, Cohen DM (2004) Renal expression of osmotically responsive cation channel TRPV4 is restricted to water-impermeant nephron segments. Am J Physiol Renal Physiol 287:F17–24
Todaka H, Taniguchi J, Satoh J, Mizuno A, Suzuki M (2004) Warm temperature-sensitive transient receptor potential vanilloid 4 (TRPV4) plays an essential role in thermal hyperalgesia. J Biol Chem 279:35133–35138
Voets T, Prenen J, Vriens J, Watanabe H, Janssens A, Wissenbach U, Bödding M, Droogmans G, Nilius B (2002) Molecular determinants of permeation through the cation channel TRPV4. J Biol Chem 277:33704–33710
Vriens J, Watanabe H, Janssens A, Droogmans G, Voets T, Nilius B (2004) Cell swelling, heat, and chemical agonists use distinct pathways for the activation of the cation channel TRPV4. Proc Natl Acad Sci USA 101:396–401
Vriens J, Owsianik G, Fisslthaler B, Suzuki M, Janssens A, Voets T, Morisseau C, Hammock BD, Fleming I, Busse R, Nilius B (2005) Modulation of the Ca2+ permeable cation channel TRPV4 by cytochrome P450 epoxygenases in vascular endothelium. Circ Res 97:908–915
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 (2002a) Activation of TRPV4 channels (hVRL-2/mTRP12) by phorbol derivatives. J Biol Chem 277:13569–13577
Watanabe H, Vriens J, Suh SH, Benham CD, Droogmans G, Nilius B (2002b) Heat-evoked activation of TRPV4 channels in an HEK293 cell expression system and in native mouse aorta endothelial cells. J Biol Chem 277:47044–47051
Watanabe H, Vriens J, Janssens A, Wondergem R, Droogmans G, Nilius B (2003a) Modulation of TRPV4 gating by intra-and extracellular Ca2+. Cell Calcium 33:489–495
Watanabe H, Vriens J, Prenen J, Droogmans G, Voets T, Nilius B (2003b) Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels. Nature 424:434–438
Wissenbach U, Bödding M, Freichel M, Flockerzi V (2000) Trp12, a novel Trp related protein from kidney. FEBS Lett 485:127–134
Xu F, Satoh E, Iijima T (2003a) Protein kinase C-mediated Ca2+ entry in HEK 293 cells transiently expressing human TRPV4. Br J Pharmacol 140:413–421
Xu H, Zhao H, Tian W, Yoshida K, Roullet JB, Cohen DM (2003b) 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 278:11520–11527
Xu H, Fu Y, Tian W, Cohen DM (2005) Glycosylation of the osmoresponsive transient receptor potential channel TRPV4 on Asn-651 influences membrane trafficking. Am J Physiol Renal Physiol 290:F1103–F1109
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2007 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Plant, T.D., Strotmann, R. (2007). TRPV4. In: Flockerzi, V., Nilius, B. (eds) Transient Receptor Potential (TRP) Channels. Handbook of Experimental Pharmacology, vol 179. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-34891-7_11
Download citation
DOI: https://doi.org/10.1007/978-3-540-34891-7_11
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-540-34889-4
Online ISBN: 978-3-540-34891-7
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)