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Keywords:

  • apoptosis;
  • 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.