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

TRPM2 is a Ca 2+ -permeable cation channel that is specifically activated by adenosine diphosphoribose (ADPR). Channel activation in the plasma membrane leads to Ca 2+ 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 ([Ca 2+ ] 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 Ca 2+ -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 IP 3 -dependent Ca 2+ release via P2Y and adenosine receptors. Thus, ADPR and TRPM2 represent multimodal signaling elements regulating Ca 2+ mobilization in β cells through membrane depolarization, Ca 2+ influx, and release of Ca 2+ from intracellular stores.