title: TRPM2 activation by cyclic ADP-ribose at body temperature is involved in insulin secretion.
abstract: There are eight thermosensitive TRP (transient receptor potential) channels in mammals, and there might be other TRP channels sensitive to temperature stimuli. Here, we demonstrate that TRPM2 can be activated by exposure to warm temperatures (>35 degrees C) apparently via direct heat-evoked channel gating. beta-NAD(+)- or ADP-ribose-evoked TRPM2 activity is robustly potentiated at elevated temperatures. We also show that, even though cyclic ADP-ribose (cADPR) does not activate TRPM2 at 25 degrees C, co-application of heat and intracellular cADPR dramatically potentiates TRPM2 activity. Heat and cADPR evoke similar responses in rat insulinoma RIN-5F cells, which express TRPM2 endogenously. In pancreatic islets, TRPM2 is coexpressed with insulin, and mild heating of these cells evokes increases in both cytosolic Ca(2+) and insulin release, which is K(ATP) channel-independent and protein kinase A-mediated. Heat-evoked responses in both RIN-5F cells and pancreatic islets are significantly diminished by treatment with TRPM2-specific siRNA. These results identify TRPM2 as a potential molecular target for cADPR, and suggest that TRPM2 regulates Ca(2+) entry into pancreatic beta-cells at body temperature depending on the production of cADPR-related molecules, thereby regulating insulin secretion.
authors.affiliation: Section of Cell Signaling, Okazaki Institute for Integrative Bioscience, National Institutes of Natural Sciences, Aichi, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Togashi
authors.forename: Yuji
authors.initials: Y
authors.lastname: Hara
authors.forename: Tomoko
authors.initials: T
authors.lastname: Tominaga
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Higashi
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Konishi
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Mori
authors.forename: Makoto
authors.initials: M
authors.lastname: Tominaga
mesh_terms: D000818:Animals; D001831:Body Temperature; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D036563:Cyclic ADP-Ribose / Q000032:analysis / Q000378:metabolism*; D006358:Hot Temperature; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D051381:Rats; D050053:TRPM Cation Channels / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D007328:Insulin; D034741:RNA, Small Interfering; D050053:TRPM Cation Channels; C121934:TRPM2 protein, human; D036563:Cyclic ADP-Ribose; D002118:Calcium