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Published online
doi:10.1083/jcb.200712058
The Journal of Cell Biology, Vol. 181, No. 1, 143-155
The Rockefeller University Press, 0021-9525 $30.00
© Fernandes et al.
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Article

IP3 sensitizes TRPV4 channel to the mechano- and osmotransducing messenger 5'-6'-epoxyeicosatrienoic acid



Jacqueline Fernandes, Ivan M. Lorenzo, Yaniré N. Andrade, Anna Garcia-Elias, Selma A. Serra, José M. Fernández-Fernández, and Miguel A. Valverde

Laboratory of Molecular Physiology and Channelopathies, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona 08003, Spain

Correspondence to M. Valverde: miguel.valverde{at}upf.edu

Mechanical and osmotic sensitivity of the transient receptor potential vanilloid 4 (TRPV4) channel depends on phospholipase A2 (PLA2) activation and the subsequent production of the arachidonic acid metabolites, epoxyeicosatrienoic acid (EET). We show that both high viscous loading and hypotonicity stimuli in native ciliated epithelial cells use PLA2–EET as the primary pathway to activate TRPV4. Under conditions of low PLA2 activation, both also use extracellular ATP-mediated activation of phospholipase C (PLC)–inositol trisphosphate (IP3) signaling to support TRPV4 gating. IP3, without being an agonist itself, sensitizes TRPV4 to EET in epithelial ciliated cells and cells heterologously expressing TRPV4, an effect inhibited by the IP3 receptor antagonist xestospongin C. Coimmunoprecipitation assays indicated a physical interaction between TRPV4 and IP3 receptor 3. Collectively, our study suggests a functional coupling between plasma membrane TRPV4 channels and intracellular store Ca2+ channels required to initiate and maintain the oscillatory Ca2+ signal triggered by high viscosity and hypotonic stimuli that do not reach a threshold level of PLA2 activation.

J. Fernandes and I.M. Lorenzo contributed equally to this paper.

Abbreviations used in this paper: 4{alpha}-PDD, 4{alpha}-phorbol 12,13-didecanoate; AA, arachidonic acid; AACOCF3, arachidonyl trifluoromethyl ketone; ANOVA, analysis of variance; CBF, ciliary beat frequency; EET, epoxyeicosatrienoic acid; IP3, inositol trisphosphate; IP3R, IP3 receptor; pBPB, 4-bromophenacyl bromide; PLA2, phospholipase A2; TRP, transient receptor potential; TRPV4, TRP vanilloid 4.


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