Functional control of cold- and menthol-sensitive TRPM8 ion channels by phosphatidylinositol 4,5-bisphosphate.
Cold is detected by a small subpopulation of peripheral thermoreceptors. TRPM8, a cloned menthol- and cold-sensitive ion channel, has been suggested to mediate cold transduction in the innocuous range. The channel shows a robust response in whole-cell recordings but exhibits markedly reduced activity in excised membrane patches. Here we report that phosphatidylinositol 4,5-bisphosphate (PIP2) is an essential regulator of the channel function. The rundown of the channel is prevented by lipid phosphatase inhibitors. Application of exogenous PIP2 both activates the channel directly and restores rundown activity. Whole-cell experiments involving intracellular dialysis with polyvalent cations, inhibition of PIP2 synthesis kinases, and receptor-mediated hydrolysis of PIP2 show that PIP2 also modulates the channel activity in the intact cells. The crucial role of PIP2 on the function of TRPM8 suggests that the membrane PIP2 level may be an important regulator of cold transduction in vivo. The opposite effects of PIP2 on the vanilloid receptor TRPV1 and TRPM8 also implies that the membrane lipid may have dual actions as a bimodal switch to selectively control the heat- and cold-induced responses in nociceptors expressing both channels.
Liu
Beiying
B
Department of Physiology and Biophysical Sciences, State University of New York at Buffalo, Buffalo, New York 14214, USA.
Qin
Feng
F
D019870:1-Phosphatidylinositol 4-Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002412:Cations / Q000494:pharmacology; D002460:Cell Line; D003080:Cold Temperature; D011756:Diphosphates / Q000493:pharmacokinetics; D005459:Fluorides / Q000493:pharmacokinetics; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000502:physiology; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology*; D017136:Ion Transport / Q000187:drug effects; D007668:Kidney; D008563:Membrane Lipids / Q000502:physiology; D008610:Menthol / Q000494:pharmacology*; D018721:Muscarinic Agonists / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000187:drug effects / Q000502:physiology*; D009865:Oocytes; D018408:Patch-Clamp Techniques; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D051381:Rats; D043643:Receptor, Muscarinic M1 / Q000187:drug effects; D020917:Receptor, trkA / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D050053:TRPM Cation Channels; D014638:Vanadates / Q000493:pharmacokinetics; D000077191:Wortmannin; D014982:Xenopus laevis
D000730:Androstadienes; D002412:Cations; D011756:Diphosphates; D007473:Ion Channels; D008563:Membrane Lipids; D018721:Muscarinic Agonists; D009363:Neoplasm Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate; D043643:Receptor, Muscarinic M1; D011993:Recombinant Fusion Proteins; D050053:TRPM Cation Channels; C425966:TRPM8 protein, human; C498947:Trpm8 protein, rat; D008610:Menthol; D014638:Vanadates; D002217:Carbachol; D019870:1-Phosphatidylinositol 4-Kinase; D020917:Receptor, trkA; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D005459:Fluorides; D000077191:Wortmannin
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