PMID:12617961

Citation	Erin, N, Bronson, SK and Billingsley, ML (2003) Calcium-dependent interaction of calcineurin with Bcl-2 in neuronal tissue. Neuroscience 117:541-55
Abstract	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.
Links	PubMed
Keywords	Animals; Blotting, Western/methods; Calcineurin/metabolism; Calcium/metabolism; Calcium Channels/drug effects; Calcium Channels/metabolism; Calmodulin/pharmacology; Cerebellum/cytology; Cerebellum/drug effects; Cerebellum/metabolism; Cerebral Cortex/drug effects; Cerebral Cortex/metabolism; Cerebral Cortex/physiopathology; Crosses, Genetic; Enzyme Inhibitors/pharmacology; Excitatory Amino Acid Agonists; Hippocampus/drug effects; Hippocampus/metabolism; Hippocampus/physiopathology; Hypoxia-Ischemia, Brain/metabolism; Hypoxia-Ischemia, Brain/physiopathology; Inositol 1,4,5-Trisphosphate Receptors; Male; Mice; Mice, Knockout/metabolism; Mice, Transgenic/metabolism; N-Methylaspartate/pharmacology; Neurons/drug effects; Neurons/metabolism; Precipitin Tests/methods; Proto-Oncogene Proteins c-bcl-2/genetics; Proto-Oncogene Proteins c-bcl-2/metabolism; Proto-Oncogene Proteins c-bcl-2/physiology; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear/drug effects; Receptors, Cytoplasmic and Nuclear/metabolism; Subcellular Fractions/classification; Subcellular Fractions/metabolism; Thapsigargin/pharmacology; Time Factors
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