Our previous study using apoptosis analysis suggested that Ca
2+ release through inositol 1,4,5-trisphosphate (IP
3) receptors and the subsequent Ca
2+ influx through store-operated channels (SOCs) constitute a triggering signal for H
2O
2-induced β-cell apoptosis. In the present study, we further examined the obligatory role of early Ca
2+ responses in β-cell apoptosis induction. H
2O
2 induced elevation of the cytosolic Ca
2+ concentration ([Ca
2+]
c) consisting of two phases: an initial transient [Ca
2+]
c elevation within 30 min and a slowly developing one thereafter. The first phase was almost abolished by 2-aminoethoxydiphenylborate (2-APB), which blocks IP
3 receptors and cation channels including SOCs, while the second phase was only partially inhibited by 2-APB. The inhibition by 2-APB of the second phase was not observed when 2-APB was added 30 min after the treatment with H
2O
2. 2-APB also largely inhibited elevation of the mitochondrial Ca
2+ concentration ([Ca
2+]
m) induced by H
2O
2 when 2-APB was applied simultaneously with H
2O
2, but not when applied 30 min after H
2O
2 application. In addition, 2-APB inhibited the release of mitochondrial cytochrome
c to the cytosol induced by H
2O
2 when 2-APB was applied simultaneously with H
2O
2 but not 30 min post-treatment. H
2O
2-induced [Ca
2+]
m elevation and cell death were not inhibited by Ru360, an inhibitor of the mitochondrial calcium uniporter (MCU). These results suggest that the H
2O
2-induced initial [Ca
2+]
c elevation, occurring within 30 min and mediated by Ca
2+ release through IP
3 receptors and subsequent Ca
2+ influx through SOCs, leads to [Ca
2+]
m elevation, possibly through a mechanism independent of MCU, thereby inducing cytochrome
c release and consequent apoptosis.
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