A modular PIP2 binding site as a determinant of capsaicin receptor sensitivity.
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.
Prescott
Elizabeth D
ED
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143-2140, USA.
Julius
David
D
D000595:Amino Acid Sequence; D000818:Animals; D001152:Arsenicals / Q000494:pharmacology; D001665:Binding Sites; D002211:Capsaicin / Q000378:metabolism / Q000494:pharmacology; D002352:Carrier Proteins; D066246:ErbB Receptors / Q000378:metabolism; D006358:Hot Temperature; D006801:Humans; D015640:Ion Channel Gating; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D009154:Mutation; D009865:Oocytes; D018408:Patch-Clamp Techniques; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D010766:Phosphorylation; D024661:Potassium Channels, Inwardly Rectifying / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D020917:Receptor, trkA / Q000378:metabolism; D011955:Receptors, Drug / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017384:Sequence Deletion; D010738:Type C Phospholipases / Q000378:metabolism; D014981:Xenopus
D001152:Arsenicals; D002352:Carrier Proteins; D008565:Membrane Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D011993:Recombinant Fusion Proteins; C029341:oxophenylarsine; D066246:ErbB Receptors; D020917:Receptor, trkA; D010738:Type C Phospholipases; D002211:Capsaicin