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.