The super-cooling agent icilin reveals a mechanism of coincidence detection by a temperature-sensitive TRP channel.
TRPM8, a member of the transient receptor potential family of ion channels, depolarizes somatosensory neurons in response to cold. TRPM8 is also activated by the cooling agents menthol and icilin. When exposed to menthol or cold, TRPM8 behaves like many ligand-gated channels, exhibiting rapid activation followed by moderate Ca(2+)-dependent adaptation. In contrast, icilin activates TRPM8 with extremely variable latency followed by extensive desensitization, provided that calcium is present. Here, we show that, to achieve full efficacy, icilin requires simultaneous elevation of cytosolic Ca2+, either via permeation through TRPM8 channels or by release from intracellular stores. Thus, two stimuli must be paired to elicit full channel activation, illustrating the potential for coincidence detection by TRP channels. Determinants of icilin sensitivity map to a region of TRPM8 that corresponds to the capsaicin binding site on the noxious heat receptor TRPV1, suggesting a conserved molecular logic for gating of these thermosensitive channels by chemical agonists.
Chuang
Huai-hu
HH
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143, USA.
Neuhausser
Werner M
WM
Julius
David
D
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology; D002645:Chickens; D003080:Cold Temperature; D000081005:Cyclohexane Monoterpenes; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D004533:Egtazic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects; D008610:Menthol / Q000494:pharmacology; D008967:Molecular Biology / Q000379:methods; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed / Q000502:physiology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D018408:Patch-Clamp Techniques / Q000379:methods; D015221:Potassium Channels / Q000378:metabolism; D024681:Potassium Channels, Calcium-Activated; D011744:Pyrimidinones / Q000494:pharmacology*; D051640:Small-Conductance Calcium-Activated Potassium Channels; D050053:TRPM Cation Channels; D013729:Terpenes / Q000494:pharmacology; D014162:Transfection / Q000379:methods; D014982:Xenopus laevis
D002614:Chelating Agents; D000081005:Cyclohexane Monoterpenes; D007473:Ion Channels; D009363:Neoplasm Proteins; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D011744:Pyrimidinones; D051640:Small-Conductance Calcium-Activated Potassium Channels; D050053:TRPM Cation Channels; C425966:TRPM8 protein, human; D013729:Terpenes; D008610:Menthol; C409816:isopulegol; D004533:Egtazic Acid; C490483:icilin; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D000109:Acetylcholine; D002118:Calcium