title: PI(4,5)P2 regulates the activation and desensitization of TRPM8 channels through the TRP domain.
abstract: 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 Ca(2+) influx through these channels activates a Ca(2+)-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.
authors.affiliation: Department of Physiology and Biophysics, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1218, New York, New York 10029, USA. tibor.rohacs@umdnj.edu <tibor.rohacs@umdnj.edu>
authors.forename: Tibor
authors.initials: T
authors.lastname: Rohács
authors.forename: Coeli M B
authors.initials: CM
authors.lastname: Lopes
authors.forename: Ioannis
authors.initials: I
authors.lastname: Michailidis
authors.forename: Diomedes E
authors.initials: DE
authors.lastname: Logothetis
mesh_terms: D000818:Animals; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002522:Chlorocebus aethiops; D003080:Cold Temperature; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008610:Menthol / Q000494:pharmacology; D009154:Mutation / Q000502:physiology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000187:drug effects / Q000502:physiology; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism*; D050916:TRPV Cation Channels; D013697:Thermosensing / Q000187:drug effects / Q000502:physiology*
chemical_list: D015220:Calcium Channels; D007473:Ion Channels; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate; D050916:TRPV Cation Channels; C492239:TRPV5 protein, human; D008610:Menthol; D002118:Calcium