In vitro hypoxia and excitotoxicity in human brain induce calcineurin-Bcl-2 interactions.

N Erin, R A W Lehman, P J Boyer, M L Billingsley

Journal: Neuroscience 2003;117(3):557-65

PMID: 12617962

Full Text on Elsevier Science View on PubMed

Abstract

Although pathogenesis of neuronal ischemia is incompletely understood, evidence indicates apoptotic neuronal death after ischemia. Bcl-2, an anti-apoptotic and neuroprotective protein, interacts with calcineurin in non-neuronal tissues. Activation of calcineurin, which is abundant in the brain, may play a role in apoptosis. Using co-immunoprecipitation experiments in biopsy-derived, fresh human cortical and hippocampal slices, we examined possible interactions between calcineurin and Bcl-2. Calcineuin-Bcl-2 interactions increased after exposure in vitro to excitotoxic agents and conditions of hypoxia/aglycia. This interaction may shuttle calcineurin to substrates such as the inositol-1,4,5-tris-phosphate receptor because under these experimental conditions interactions between calcineurin and inositol-1,4,5-tris-phosphate receptor also increased. A specific calcineurin inhibitor, FK-520, attenuated insult-induced increases in calcineurin-Bcl-2 interactions and augmented caspase-3 like activity. These data suggest that Bcl-2 modulates neuroprotective effects of calcineurin and that calcineurin inhibitors increase ischemic neuronal damage.

Address: Department of Pharmacology, H078, 500 University Drive, Pennsylvania State University, College of Medicine, Hershey, PA 17033, USA.

DOI: 10.1016/s0306-4522(02)00934-x

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MeSH Terms: Adult, Blotting, Western, Calcineurin, Calcium Channels, Caspase 3, Caspases, Cerebral Cortex, Enzyme Inhibitors, Enzyme Precursors, Female, Humans, Hypoxia, Brain, Immunosuppressive Agents, In Vitro Techniques, Inositol 1,4,5-Trisphosphate Receptors, Kainic Acid, Male, Middle Aged, N-Methylaspartate, Neurotoxins, Okadaic Acid, Precipitin Tests, Proto-Oncogene Proteins c-bcl-2, Receptors, Cytoplasmic and Nuclear, Spectrin, Tacrolimus