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Isolated Pancreatic Islet Treatment and Apoptosis Measurement
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RyR2 and calpain-10 delineate a novel apoptosis pathway in pancreatic islets

James D Johnson1, Zhiqiang Han, Kenichi Otani

  • 1Department of Internal Medicine, Washington University, St. Louis, Missouri 63110, USA.

The Journal of Biological Chemistry
|March 27, 2004
PubMed

Insights

Inhibiting the type 2 ryanodine receptor (RyR2) in pancreatic beta-cells increased apoptosis via calpain-10, a type 2 diabetes gene. RyR2 activity suppresses this cell death pathway, crucial for beta-cell survival.

Area of Science:

  • Cell Biology
  • Endocrinology
  • Molecular Biology

Background:

  • Cellular apoptosis is triggered by disruptions in signaling and metabolic pathways.
  • The type 2 ryanodine receptor (RyR2) is implicated in cellular survival mechanisms.

Purpose of the Study:

  • To investigate the mechanism of apoptosis induced by RyR2 inhibition in pancreatic beta-cells.
  • To identify the specific pathways and molecules involved in this programmed cell death.

Main Methods:

  • Utilized pharmacological and genetic approaches to inhibit RyR2 in human and mouse pancreatic beta-cells.
  • Assessed apoptosis, caspase-3 activation, and calpain activity and expression.
  • Investigated the role of calpain-10 isoform in ryanodine-induced apoptosis.

Main Results:

  • Inhibition of RyR2 markedly increased apoptosis in pancreatic beta-cells, independent of caspase-3.
  • Increased calpain activity and gene expression suggested a calpain-dependent pathway.
  • Calpain-10 was identified as the mediator of ryanodine-induced apoptosis.
  • Apoptosis induced by palmitate and low glucose also required calpain-10.
  • Ryanodine-induced apoptosis was reversed by glucagon-like peptide or high glucose.

Conclusions:

  • RyR2 activity is essential for beta-cell survival in vitro by suppressing a calpain-10-mediated death pathway.
  • Calpain-10, a type 2 diabetes susceptibility gene, plays a critical role in beta-cell apoptosis.
  • Modulating RyR2 activity or calpain-10 could offer therapeutic strategies for diabetes.

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