Affiliation:
1. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143–2140, USA.
Abstract
The capsaicin receptor (TRPV1), a heat-activated ion channel of the pain pathway, is sensitized by phosphatidylinositol-4,5-bisphosphate (PIP
2
) hydrolysis after phospholipase C activation. We identify a site within the C-terminal domain of TRPV1 that is required for PIP
2
-mediated inhibition of channel gating. Mutations that weaken PIP
2
-TRPV1 interaction reduce thresholds for chemical or thermal stimuli, whereas TRPV1 channels in which this region is replaced with a lipid-binding domain from PIP
2
-activated potassium channels remain inhibited by PIP
2
. The PIP
2
-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.
Publisher
American Association for the Advancement of Science (AAAS)
Cited by
469 articles.
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