Caspase‐3‐truncated type 1 inositol 1,4,5‐trisphosphate receptor enhances intracellular Ca 2+ leak and disturbs Ca 2+ signalling

Background information . The IP 3 R (inositol 1,4,5‐trisphosphate receptor) is a tetrameric channel that accounts for a large part of the intracellular Ca 2+ release in virtually all cell types. We have previously demonstrated that caspase‐3‐mediated cleavage of IP 3 R1 during cell death generates a C‐terminal fragment of 95 kDa comprising the complete channel domain. Expression of this truncated IP 3 R 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 IP 3 R1 increased the rate of thapsigargin‐mediated Ca 2+ leak and decreased the rate of Ca 2+ uptake into the ER (endoplasmic reticulum), although it was not sufficient by itself to deplete intracellular Ca 2+ stores. We detected the truncated IP 3 R1 in different cell types after a challenge with apoptotic stimuli, as well as in aged mouse oocytes. Injection of mRNA corresponding to the truncated IP 3 R1 blocked sperm factor‐induced Ca 2+ oscillations and induced an apoptotic phenotype. Conclusions . In the present study, we show that caspase‐3‐mediated truncation of IP 3 R1 enhanced the Ca 2+ leak from the ER. We suggest a model in which, in normal conditions, the increased Ca 2+ leak is largely compensated by enhanced Ca 2+ ‐uptake activity, whereas in situations where the cellular metabolism is compromised, as occurring in aging oocytes, the Ca 2+ leak acts as a feed‐forward mechanism to divert the cell into apoptosis.