Caspase 3 cleavage of the inositol 1,4,5-trisphosphate receptor does not contribute to apoptotic calcium release

Askar M. Akimzhanov, José M. Barral, Darren Boehning

    Research output: Contribution to journalArticle

    16 Scopus citations

    Abstract

    An important role in the regulation of apoptotic calcium release is played by the ubiquitously expressed family of inositol 1,4,5-trisphosphate receptor (IP3R) channels. One model for IP3R activation during apoptosis is cleavage by the apoptotic protease caspase 3. Here we show that early elevations in cytosolic calcium during apoptosis do not require caspase 3 activity. We detected a robust increase in calcium levels in response to staurosporine treatment in primary human fibroblasts and HeLa cells in the presence of the caspase inhibitor Z-VAD, indicating that calcium release during the initiation of apoptosis occurs independently of caspase 3. Similar results were obtained with MCF-7 cells which lack caspase 3 expression. Stable expression of caspase 3 in MCF-7 cells and TAT-based transduction of the active recombinant caspase 3 directly into living MCF-7 cells had marginal effects on the early events leading to cytosolic calcium elevations and irreversible commitment to apoptotic cell death. Significantly, blocking IP3 binding to the IP3R with an IP3 sponge resulted in suppression of staurosporine-induced calcium release and cell death. Collectively, our results suggest that generation of IP3 is sufficient for the initiation of apoptotic calcium signaling, and caspase 3-mediated truncation of IP3R channel is a consequence, not causative, of apoptotic calcium release.

    Original languageEnglish (US)
    Pages (from-to)152-158
    Number of pages7
    JournalCell Calcium
    Volume53
    Issue number2
    DOIs
    StatePublished - Feb 2013

    Keywords

    • Apoptosis
    • Calcium
    • Caspase 3
    • Inositol 1,4,5-trisphosphate receptor
    • Staurosporine

    ASJC Scopus subject areas

    • Physiology
    • Molecular Biology
    • Cell Biology

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