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

TRPM2-mediated Ca2+ release from lysosomal stores contributes to pancreatic β cell death in response to oxidative stress. Coordinating Calcium Signals TRPM2 (transient receptor potential channel, melastatin subfamily type 2) is a Ca2+-permeable ion channel found in the plasma membrane, whose activation by adenosine diphosphoribose and other adenine dinucleotides can lead to apoptosis. Lange et al. now show that TRPM2 is present in lysosomes, where it can be activated by adenosine diphosphoribose to release Ca2+ from internal stores. Moreover, both plasma membrane and lysosomal TRPM2 played crucial roles in mediating pancreatic β cell death in response to peroxide, a process thought to be involved in the development of diabetes. Although adenosine diphosphoribose acts intracellularly to activate both pools of TRPM2, the authors found that it also acts extracellularly through two classes of G protein–coupled receptors to elicit Ca2+ release from intracellular stores through a distinct pathway that was independent of TRPM2. Thus, both TRPM2 and adenosine diphosphoribose play dual roles in increasing cytoplasmic Ca2+ in pancreatic β cells. 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.