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J. Biol. Chem., Vol. 283, Issue 46, 31284-31288, November 14, 2008

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IP₃ Receptor Binds to and Sensitizes TRPV4 Channel to Osmotic Stimuli via a Calmodulin-binding Site^*

From the Laboratory of Molecular Physiology and Channelopathies, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Edifici PRBB, C/Dr. Aiguader 88, Barcelona 08003, Spain

Activation of the non-selective cation channel TRPV4 by mechanical and osmotic stimuli requires the involvement of phospholipase A₂ and the subsequent production of the arachidonic acid metabolites, epoxieicosatrienoic acids (EET). Previous studies have shown that inositol trisphosphate (IP₃) sensitizes TRPV4 to mechanical, osmotic, and direct EET stimulation. We now search for the IP₃ receptor-binding site on TRPV4 and its relevance to IP₃-mediated sensitization. Three putative sites involved in protein-protein interactions were evaluated: a proline-rich domain (PRD), a calmodulin (CaM)-binding site, and the last four amino acids (DAPL) that show a PDZ-binding motif-like. TRPV4-CaM-(812–831) channels preserved activation by hypotonicity, 4-phorbol 12,13-didecanoate, and EET but lost their physical interaction with IP₃ receptor 3 and IP₃-mediated sensitization. Deletion of a PDZ-binding motif-like (TRPV4-DAPL) did not affect channel activity or IP₃-mediated sensitization, whereas TRPV4-PRD-(132–144) resulted in loss of channel function despite correct trafficking. We conclude that IP₃-mediated sensitization requires IP₃ receptor binding to a TRPV4 C-terminal domain that overlaps with a previously described calmodulin-binding site.

Received for publication, September 10, 2008

^* This work was supported by grants from the Spanish Ministries of Education and Science (Grant SAF2006-04973 and SAF2006-13893-C02-02), Spanish Ministries of Health (Fondo de Investigación Sanitaria, Red HERACLES RD06/0009), Generalitat de Catalunya (SGR05-266), and Fundació la Marató de TV3 (061331). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Laboratory of Molecular Physiology and Channelopathies, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, C/Dr. Aiguader 88, Barcelona 08003, Spain, Tel.: 34-93-3160853; Fax: 34-93-3160901; E-mail: miguel.valverde{at}upf.edu.

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