title: Caspase-3-truncated type 1 inositol 1,4,5-trisphosphate receptor enhances intracellular Ca2+ leak and disturbs Ca2+ signalling.
abstract: BACKGROUND
  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.
authors.affiliation: Laboratory of Molecular and Cellular Signalling, Division of Physiology, Department of Molecular Cell Biology, K.U. Leuven, Campus Gasthuisberg, O&N1 bus 802, B-3000 Leuven, Belgium.
authors.forename: Leen
authors.initials: L
authors.lastname: Verbert
authors.forename: Bora
authors.initials: B
authors.lastname: Lee
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Kocks
authors.forename: Zerihun
authors.initials: Z
authors.lastname: Assefa
authors.forename: Jan B
authors.initials: JB
authors.lastname: Parys
authors.forename: Ludwig
authors.initials: L
authors.lastname: Missiaen
authors.forename: Geert
authors.initials: G
authors.lastname: Callewaert
authors.forename: Rafael A
authors.initials: RA
authors.lastname: Fissore
authors.forename: Humbert
authors.initials: H
authors.lastname: De Smedt
authors.forename: Geert
authors.initials: G
authors.lastname: Bultynck
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000378:metabolism; D005260:Female; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism*; D008540:Meiosis / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009865:Oocytes / Q000166:cytology / Q000502:physiology; D019311:Staurosporine / Q000378:metabolism; D019284:Thapsigargin / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D053496:Inositol 1,4,5-Trisphosphate Receptors; D019284:Thapsigargin; D053148:Caspase 3; D019311:Staurosporine; D002118:Calcium