Article
- The EMBO Journal (2006) 25, 1804 - 1815
- doi:10.1038/sj.emboj.7601083
Published online: 6 April 2006
Subject Category:
TRPM2 activation by cyclic ADP-ribose at body temperature is involved in insulin secretion
Kazuya Togashi1,2, Yuji Hara3, Tomoko Tominaga1,2, Tomohiro Higashi1,2, Yasunobu Konishi4, Yasuo Mori3 and Makoto Tominaga1,2
- Section of Cell Signaling, Okazaki Institute for Integrative Bioscience, National Institutes of Natural Sciences, Okazaki, Aichi, Japan
- Department of Physiological Sciences, The Graduate University for Advanced Studies, Okazaki, Japan
- Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan
- Department of Cellular and Molecular Physiology, Mie University School of Medicine, Mie, Japan
Correspondence to:
Makoto Tominaga, Section of Cell Signaling, Okazaki Institute for Integrative Bioscience, National Institutes of Natural Sciences, Higashiyama 5-1, Myodaiji, Okazaki, Aichi 444-8787, Japan. Tel.: +81 564 59 5286; Fax: +81 564 59 5285; E-mail: tominaga@nips.ac.jp
Received 5 August 2005; Accepted 16 March 2006
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°C) apparently via direct heat-evoked channel gating. 
-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°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 Ca2+ and insulin release, which is KATP 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 Ca2+ entry into pancreatic -cells at body temperature depending on the production of cADPR-related molecules, thereby regulating insulin secretion.
Keywords:
- cyclic ADP-ribose,
- insulin,
- temperature,
- TRPM2
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