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Sci. Signal., 19 May 2009
Vol. 2, Issue 71, p. ra23
[DOI: 10.1126/scisignal.2000278]

RESEARCH ARTICLES

TRPM2 Functions as a Lysosomal Ca2+-Release Channel in β Cells

Ingo Lange1,2, Shinichiro Yamamoto3, Santiago Partida-Sanchez4,5, Yasuo Mori3, Andrea Fleig1,2, and Reinhold Penner1,2*

1 Center for Biomedical Research, The Queen’s Medical Center, Honolulu, HI 96813, USA.
2 John A. Burns School of Medicine at the University of Hawaii, Honolulu, HI 96813, USA.
3 Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan.
4 The Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA.
5 The Ohio State University College of Medicine, Columbus, OH 43205, USA.

Abstract: TRPM2 is a Ca2+-permeable cation channel that is specifically activated by adenosine diphosphoribose (ADPR). Channel activation in the plasma membrane leads to Ca2+ influx and has been linked to apoptotic mechanisms. The primary agonist, ADPR, is produced both extra- and intracellularly and causes increases in intracellular calcium concentration ([Ca2+]i), but the mechanisms involved are not understood. Using short interfering RNA and a knockout mouse, we report that TRPM2, in addition to its role as a plasma membrane channel, also functions as a Ca2+-release channel activated by intracellular ADPR in a lysosomal compartment. We show that both functions of TRPM2 are critically linked to hydrogen peroxide–induced β cell death. Additionally, extracellular ADPR production by the ectoenzyme CD38 from its substrates NAD+ (nicotinamide adenine dinucleotide) or cADPR causes IP3-dependent Ca2+ release via P2Y and adenosine receptors. Thus, ADPR and TRPM2 represent multimodal signaling elements regulating Ca2+ mobilization in β cells through membrane depolarization, Ca2+ influx, and release of Ca2+ from intracellular stores.

* To whom correspondence should be addressed. E-mail: rpenner{at}hawaii.edu

Citation: I. Lange, S. Yamamoto, S. Partida-Sanchez, Y. Mori, A. Fleig, R. Penner, TRPM2 Functions as a Lysosomal Ca2+-Release Channel in β Cells. Sci. Signal. 2, ra23 (2009).

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