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Functional Recovery from Desensitization of Vanilloid Receptor TRPV1 Requires Resynthesis of Phosphatidylinositol 4,5-Bisphosphate

Capsaicin and other naturally occurring pungent molecules have long been used as topical analgesics to treat a variety of chronic pain conditions. The analgesic effects of these compounds involve long-term desensitization of nociceptors after strong stimulation. To elucidate the underlying mechanisms, we studied the recovery from desensitization of the vanilloid receptor TRPV1. We showed that prolonged applications of capsaicin led to nearly complete desensitization of the channel and that its functional recovery from desensitization required a high concentration of intracellular ATP. Nonhydrolyzable ATP analogs did not substitute for ATP to promote recovery. Neither inhibition nor activation of protein kinases prevented recovery of the channel from desensitization. In contrast, blockade of lipid kinases, in particular phosphatidylinositol-4-kinase, abolished recovery, as did activation of membrane receptors that stimulate hydrolysis of phosphatidylinositol 4,5-biphosphate (PIP2). Additional experiments using the PIP2-sensitive inward rectifier potassium channel Kir2.1 as a biosensor showed a high degree of temporal correlation between the two channels on both functional suppression after capsaicin stimulation and subsequent recovery. These data suggest that depletion of PIP2 occurs concomitantly with activation of TRPV1 and its replenishment in the membrane determines recovery of the channel from desensitization. In addition to revealing a new role of phosphoinositide signaling in regulation of nociception, our results provide novel insight into the topical mechanisms of the analgesic effects of capsaicin and the strategies to improve its effectiveness.