TRPM2 functions as a lysosomal Ca2+-release channel in beta cells
Ingo Lange1, Shinichiro Yamamoto, Santiago Partida-Sanchez
1Center for Biomedical Research, The Queen's Medical Center, Honolulu, HI 96813, USA.
Science Signaling
|May 21, 2009
Summary
Adenosine diphosphoribose (ADPR) activates TRPM2 channels in beta cells, causing calcium influx and release. This dual function is critical for hydrogen peroxide-induced beta cell death.
Area of Science:
- Cell Biology
- Calcium Signaling
- Ion Channels
Background:
- TRPM2 is a calcium-permeable cation channel activated by adenosine diphosphoribose (ADPR).
- ADPR's role in intracellular calcium concentration ([Ca2+]i) increases is not fully understood.
- TRPM2's plasma membrane function is linked to apoptotic mechanisms.
Purpose of the Study:
- To investigate the dual role of TRPM2 in calcium mobilization within beta cells.
- To elucidate the mechanisms linking TRPM2, ADPR, and beta cell death.
- To understand the regulation of extracellular ADPR production and its downstream effects.
Main Methods:
- Utilized short interfering RNA (siRNA) and a TRPM2 knockout mouse model.
- Investigated TRPM2 function in both plasma membrane and lysosomal compartments.
- Examined the role of CD38 in extracellular ADPR production from NAD+ and cADPR.
Main Results:
- TRPM2 functions as both a plasma membrane Ca2+ influx channel and a lysosomal Ca2+-release channel activated by intracellular ADPR.
- Both TRPM2 functions are essential for hydrogen peroxide-induced beta cell death.
- Extracellular ADPR, produced by CD38, triggers IP3-dependent Ca2+ release via P2Y and adenosine receptors.
Conclusions:
- TRPM2 and ADPR are multimodal signaling elements regulating beta cell calcium homeostasis.
- TRPM2 mediates both Ca2+ influx and release from intracellular stores in response to ADPR.
- These mechanisms are critical for beta cell survival and death pathways.
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