期刊
NATURE NEUROSCIENCE
卷 8, 期 5, 页码 626-634出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nn1451
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资金
- NHLBI NIH HHS [HL59949] Funding Source: Medline
The subjective feeling of cold is mediated by the activation of TRPM8 channels in thermoreceptive neurons by cold or by cooling agents such as menthol. Here, we demonstrate a central role for phosphatidylinositol 4,5-bisphosphate (PI(4,5)P-2) in the activation of recombinant TRPM8 channels by both cold and menthol. Moreover, we show that Ca2+ influx through these channels activates a Ca2+-sensitive phospholipase C and that the subsequent depletion of PI(4,5)P-2 limits channel activity, serving as a unique mechanism for desensitization of TRPM8 channels. Finally, we find that mutation of conserved positive residues in the highly conserved proximal C-terminal TRP domain of TRPM8 and two other family members, TRPM5 and TRPV5, reduces the sensitivity of the channels for PI(4,5)P-2 and increases inhibition by PI(4,5)P-2 depletion. These data suggest that the TRP domain of these channels may serve as a PI(4,5)P-2-interacting site and that regulation by PI(4,5)P-2 is a common feature of members of the TRP channel family.
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