Interaction with phosphoinositides confers adaptation onto the TRPV1 pain receptor.
Adaptation is a common feature of many sensory systems. But its occurrence to pain sensation has remained elusive. Here we address the problem at the receptor level and show that the capsaicin ion channel TRPV1, which mediates nociception at the peripheral nerve terminals, possesses properties essential to the adaptation of sensory responses. Ca(2+) influx following the channel opening caused a profound shift (approximately 14-fold) of the agonist sensitivity, but did not alter the maximum attainable current. The shift was adequate to render the channel irresponsive to normally saturating concentrations, leaving the notion that the channel became no longer functional after desensitization. By simultaneous patch-clamp recording and total internal reflection fluorescence (TIRF) imaging, it was shown that the depletion of phosphatidylinositol 4,5-bisphosphate (PIP2) induced by Ca(2+) influx had a rapid time course synchronous to the desensitization of the current. The extent of the depletion was comparable to that by rapamycin-induced activation of a PIP2 5-phosphatase, which also caused a significant reduction of the agonist sensitivity without affecting the maximum response. These results support a prominent contribution of PIP2 depletion to the desensitization of TRPV1 and suggest the adaptation as a possible physiological function for the Ca(2+) influx through the channel.
Yao
Jing
J
Department of Physiology and Biophysical Sciences, State University of New York at Buffalo, Buffalo, NY, USA.
Qin
Feng
F
D000222:Adaptation, Physiological / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002211:Capsaicin / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D051381:Rats; D020123:Sirolimus / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000378:metabolism*
D019269:Phosphatidylinositol 4,5-Diphosphate; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D010744:Phosphoric Monoester Hydrolases; D002211:Capsaicin; D020123:Sirolimus