TRPM2 functions as a lysosomal Ca2+-release channel in beta 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 beta 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 beta cells through membrane depolarization, Ca2+ influx, and release of Ca2+ from intracellular stores.
Lange
Ingo
I
Center for Biomedical Research, The Queen's Medical Center, Honolulu, HI 96813, USA.
Yamamoto
Shinichiro
S
Partida-Sanchez
Santiago
S
Mori
Yasuo
Y
Fleig
Andrea
A
Penner
Reinhold
R
D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics / Q000378:metabolism; D000246:Adenosine Diphosphate Ribose / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005455:Fluorescent Antibody Technique; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D058906:Purinergic P1 Receptor Agonists; D058910:Purinergic P2 Receptor Agonists; D034622:RNA Interference; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D014162:Transfection
D008562:Membrane Glycoproteins; D058906:Purinergic P1 Receptor Agonists; D058910:Purinergic P2 Receptor Agonists; D018047:Receptors, Purinergic P1; D018048:Receptors, Purinergic P2; D050053:TRPM Cation Channels; C121934:TRPM2 protein, human; C544443:TRPM2 protein, mouse; D000246:Adenosine Diphosphate Ribose; D006861:Hydrogen Peroxide; C498155:Cd38 protein, mouse; D051997:ADP-ribosyl Cyclase 1; D002118:Calcium