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J. Biol. Chem., Vol. 283, Issue 38, 26208-26216, September 19, 2008

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Determinants of Molecular Specificity in Phosphoinositide Regulation

PHOSPHATIDYLINOSITOL (4,5)-BISPHOSPHATE (PI(4,5)P₂) IS THE ENDOGENOUS LIPID REGULATING TRPV1^*

From the Department of Physiology and Biophysics, University of Washington, Seattle, Washington 98195-7290

Once thought of as simply an oily barrier that maintains cellular integrity, lipids are now known to play an active role in a large variety of cellular processes. Phosphoinositides are of particular interest because of their remarkable ability to affect many signaling pathways. Ion channels and transporters are an important target of phosphoinositide signaling, but identification of the specific phosphoinositides involved has proven elusive. TRPV1 is a good example; although phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P₂) can potently regulate its activation, we show that phosphatidylinositol (4)-phosphate (PI(4)P) and phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P₃) can as well. To determine the identity of the endogenous phosphoinositide regulating TRPV1, we applied recombinant pleckstrin homology domains to inside-out excised patches. Although a PI(4,5)P₂-specific pleckstrin homology domain inhibited TRPV1, a PI(3,4,5)P₃-specific pleckstrin homology domain had no effect. Simultaneous confocal imaging and electrophysiological recording of whole cells expressing a rapamycin-inducible lipid phosphatase also demonstrates that depletion of PI(4,5)P₂ inhibits capsaicin-activated TRPV1 current; the PI(4)P generated by the phosphatases was not sufficient to support TRPV1 function. We conclude that PI(4,5)P₂, and not other phosphoinositides or other lipids, is the endogenous phosphoinositide regulating TRPV1 channels.

Received for publication, March 10, 2008 , and in revised form, June 4, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant R01EY017564 from the NEI (to S. E. G.). This work was also supported by the University of Washington Vision Training Grant 2T32EY007031-31 (to R. M. K.) and the University of Washington Molecular Neuroscience Training Grant 5T32NS007332-19 (to C. A. U.). 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 two supplemental movies.

¹ Both authors contributed equally to the paper.

² To whom correspondence should be addressed: University of Washington, Box 357290, Seattle, WA 98195. E-mail: seg{at}u.washington.edu.

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