Calcium-dependent interaction of calcineurin with Bcl-2 in neuronal tissue.
Calcineurin, a calmodulin-dependent protein phosphatase, regulates transcription and possibly apoptosis. Previous studies demonstrated that in baby hamster kidney-21 cells after co-transfection calcineurin interacts with Bcl-2, thereby altering transcription and apoptosis. Using co-immunoprecipitation and subcellular fractionation techniques, we observed that calcineurin occurred as a complex with Bcl-2 in various regions of ... rat and mouse brain. The calcineurin-Bcl-2 complex was identified in mitochondrial, nuclear, microsomal and cytosol fractions. In vitro induction of hypoxia and aglycia or N-methyl-D-aspartate treatment markedly altered both extent of complex formation and its subcellular localization. These observations suggest that Bcl-2 either sequesters calcineurin, that calcineurin dephosphorylates Bcl-2, or that Bcl-2 shuttles calcineurin to specific substrates. Calcineurin also co-immunoprecipitated with the inositol-tris-phosphate receptor. This interaction increased after in vitro hypoxia/aglycia. In Bcl-2 (-/-) mice, interactions between calcineurin- and inositol-tris-phosphate receptor occurred less frequently than in wild-type mice under both control and hypoxic conditions. Experiments involving cell-free systems, as well as brain slices treated with thapsigargin or with N-methyl-D-aspartate suggested that calcium and calmodulin activation of calcineurin leads to interactions between calcineurin and Bcl-2. These data indicate that during times of cellular stress and damage, Bcl-2 targets activated calcineurin to specific compartments and substrates.
Mesh Terms:
Animals, Blotting, Western, Calcineurin, Calcium, Calcium Channels, Calmodulin, Cerebellum, Cerebral Cortex, Crosses, Genetic, Enzyme Inhibitors, Excitatory Amino Acid Agonists, Hippocampus, Hypoxia-Ischemia, Brain, Inositol 1,4,5-Trisphosphate Receptors, Male, Mice, Mice, Knockout, Mice, Transgenic, N-Methylaspartate, Neurons, Precipitin Tests, Proto-Oncogene Proteins c-bcl-2, Rats, Rats, Sprague-Dawley, Receptors, Cytoplasmic and Nuclear, Subcellular Fractions, Thapsigargin, Time Factors
Animals, Blotting, Western, Calcineurin, Calcium, Calcium Channels, Calmodulin, Cerebellum, Cerebral Cortex, Crosses, Genetic, Enzyme Inhibitors, Excitatory Amino Acid Agonists, Hippocampus, Hypoxia-Ischemia, Brain, Inositol 1,4,5-Trisphosphate Receptors, Male, Mice, Mice, Knockout, Mice, Transgenic, N-Methylaspartate, Neurons, Precipitin Tests, Proto-Oncogene Proteins c-bcl-2, Rats, Rats, Sprague-Dawley, Receptors, Cytoplasmic and Nuclear, Subcellular Fractions, Thapsigargin, Time Factors
Neuroscience
Date: Mar. 06, 2003
PubMed ID: 12617961
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