PT  - JOURNAL ARTICLE
AU  - Lange, Ingo
AU  - Yamamoto, Shinichiro
AU  - Partida-Sanchez, Santiago
AU  - Mori, Yasuo
AU  - Fleig, Andrea
AU  - Penner, Reinhold
TI  - TRPM2 Functions as a Lysosomal Ca<sup>2+</sup>-Release Channel in β Cells
AID  - 10.1126/scisignal.2000278
DP  - 2009 May 19
TA  - Science Signaling
PG  - ra23--ra23
VI  - 2
IP  - 71
4099  - http://stke.sciencemag.org/content/2/71/ra23.short
4100  - http://stke.sciencemag.org/content/2/71/ra23.full
SO  - Sci. Signal.2009 May 19; 2
AB  - 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.