Institut für Herz- und Kreislaufphysiologie, Heinrich-Heine-Universität, Universitätstr. 1, D-40225 Düsseldorf, Germany.
Caspase-3-truncated type 1 inositol 1,4,5-trisphosphate receptor enhances intracellular Ca2+ leak and disturbs Ca2+ signalling
Version of Record online: 9 JAN 2012
2008 Société Française des Microscopies and Société Biologie Cellulaire de France
Biology of the Cell
Volume 100, Issue 1, pages 39–49, January 2008
How to Cite
Verbert, L., Lee, B., Kocks, S. L., Assefa, Z., Parys, J. B., Missiaen, L., Callewaert, G., Fissore, R. A., De Smedt, H. and Bultynck, G. (2008), Caspase-3-truncated type 1 inositol 1,4,5-trisphosphate receptor enhances intracellular Ca2+ leak and disturbs Ca2+ signalling. Biology of the Cell, 100: 39–49. doi: 10.1042/BC20070086
- Issue online: 9 JAN 2012
- Version of Record online: 9 JAN 2012
- Received 21 August 2007; Accepted 28 August 2007
- calcium leak;
- calcium oscillation;
- caspase 3;
- inositol 1,4,5-trisphosphate receptor (IP3R)
Background information. The IP3R (inositol 1,4,5-trisphosphate receptor) is a tetrameric channel that accounts for a large part of the intracellular Ca2+ release in virtually all cell types. We have previously demonstrated that caspase-3-mediated cleavage of IP3R1 during cell death generates a C-terminal fragment of 95 kDa comprising the complete channel domain. Expression of this truncated IP3R increases the cellular sensitivity to apoptotic stimuli, and it was postulated to be a constitutively active channel.
Results. In the present study, we demonstrate that expression of the caspase-3-cleaved C-terminus of IP3R1 increased the rate of thapsigargin-mediated Ca2+ leak and decreased the rate of Ca2+ uptake into the ER (endoplasmic reticulum), although it was not sufficient by itself to deplete intracellular Ca2+ stores. We detected the truncated IP3R1 in different cell types after a challenge with apoptotic stimuli, as well as in aged mouse oocytes. Injection of mRNA corresponding to the truncated IP3R1 blocked sperm factor-induced Ca2+ oscillations and induced an apoptotic phenotype.
Conclusions. In the present study, we show that caspase-3-mediated truncation of IP3R1 enhanced the Ca2+ leak from the ER. We suggest a model in which, in normal conditions, the increased Ca2+ leak is largely compensated by enhanced Ca2+-uptake activity, whereas in situations where the cellular metabolism is compromised, as occurring in aging oocytes, the Ca2+ leak acts as a feed-forward mechanism to divert the cell into apoptosis.