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Science 300 (5623): 1284-1288

Copyright © 2003 by the American Association for the Advancement of Science

A Modular PIP2 Binding Site as a Determinant of Capsaicin Receptor Sensitivity

Elizabeth D. Prescott, and David Julius*

Abstract: The capsaicin receptor (TRPV1), a heat-activated ion channel of the pain pathway, is sensitized by phosphatidylinositol-4,5-bisphosphate (PIP2) hydrolysis after phospholipase C activation. We identify a site within the C-terminal domain of TRPV1 that is required for PIP2-mediated inhibition of channel gating. Mutations that weaken PIP2-TRPV1 interaction reduce thresholds for chemical or thermal stimuli, whereas TRPV1 channels in which this region is replaced with a lipid-binding domain from PIP2-activated potassium channels remain inhibited by PIP2. The PIP2-interaction domain therefore serves as a critical determinant of thermal threshold and dynamic sensitivity range, tuning TRPV1, and thus the sensory neuron, to appropriately detect heat under normal or pathophysiological conditions.

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143–2140, USA.

* To whom correspondence should be addressed. E-mail: julius{at}cmp.ucsf.edu

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