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Live Cell Calcium Imaging Combined with siRNA Mediated Gene Silencing Identifies Ca2+ Leak Channels in the ER Membrane and their Regulatory Mechanisms
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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
PubMed

Insights

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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