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J. Biol. Chem., Vol. 283, Issue 10, 6272-6280, March 7, 2008

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Stimulus-specific Modulation of the Cation Channel TRPV4 by PACSIN 3^*

Dieter D'hoedt¹, Grzegorz Owsianik, Jean Prenen, Math Pham Cuajungco^¶, Christian Grimm, Stefan Heller, Thomas Voets, and Bernd Nilius

From the Department of Physiology, Katholieke Universiteit Leuven, Campus Gasthuisberg, O&N 1, Herestraat 49 Bus 802, Leuven B-3000, Belgium, the Department of Otolaryngology, Head and Neck Surgery and Molecular & Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, and ^¶California State University, Department of Biological Science, MH-207G, Fullerton, California 92831

TRPV4, a member of the vanilloid subfamily of the transient receptor potential (TRP) channels, is activated by a variety of stimuli, including cell swelling, moderate heat, and chemical compounds such as synthetic 4-phorbol esters. TRPV4 displays a widespread expression in various cells and tissues and has been implicated in diverse physiological processes, including osmotic homeostasis, thermo- and mechanosensation, vasorelaxation, tuning of neuronal excitability, and bladder voiding. The mechanisms that regulate TRPV4 in these different physiological settings are currently poorly understood. We have recently shown that the relative amount of TRPV4 in the plasma membrane is enhanced by interaction with the SH3 domain of PACSIN 3, a member of the PACSIN family of proteins involved in synaptic vesicular membrane trafficking and endocytosis. Here we demonstrate that PACSIN 3 strongly inhibits the basal activity of TRPV4 and its activation by cell swelling and heat, while leaving channel gating induced by the synthetic ligand 4-phorbol 12,13-didecanoate unaffected. A single proline mutation in the SH3 domain of PACSIN 3 abolishes its inhibitory effect on TRPV4, indicating that PACSIN 3 must bind to the channel to modulate its function. In line herewith, mutations at specific proline residues in the N terminus of TRPV4 abolish binding of PACSIN 3 and render the channel insensitive to PACSIN 3-induced inhibition. Taken together, these data suggest that PACSIN 3 acts as an auxiliary protein of TRPV4 channel that not only affects the channel's subcellular localization but also modulates its function in a stimulus-specific manner.

Received for publication, August 2, 2007 , and in revised form, November 21, 2007.

^* This work was supported by the Human Frontiers Science Program (Grant RGP 32/2004), the Belgian Federal Government (Grant IUAP P5/05), the Research Foundation-Flanders (Grants G.0136.00, G.0172.03, and G.0565.07), the Research Council of the KU Leuven (Grants GOA 2004/07 and EF/95/010), and National Institutes of Health Grant DC004563. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ To whom correspondence should be addressed. Tel.: 32-16-330-234; Fax: 32-16-345-991; E-mail: dieter.dhoedt{at}med.kuleuven.be.

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