In vitro hypoxia and excitotoxicity in human brain induce calcineurin–bcl-2 interactions

• Published in: Neuroscience Vol. 117; no. 3; pp. 557 - 565
• Main Authors: Erin, N, Lehman, R.A.W, Boyer, P.J, Billingsley, M.L
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.01.2003; Elsevier
• Subjects: Adult; aglycia; Bcl-2; Biological and medical sciences; Blotting, Western; calcineurin; Calcineurin - metabolism; Calcium Channels - drug effects; Calcium Channels - metabolism; Caspase 3; Caspases - drug effects; Caspases - metabolism; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Enzyme Inhibitors - pharmacology; Enzyme Precursors - drug effects; Enzyme Precursors - metabolism; Female; Humans; hypoxia; Hypoxia, Brain - drug therapy; Hypoxia, Brain - metabolism; Hypoxia, Brain - physiopathology; Immunosuppressive Agents - therapeutic use; In Vitro Techniques; Inositol 1,4,5-Trisphosphate Receptors; ischemia; Kainic Acid - analogs & derivatives; Kainic Acid - pharmacology; Male; Medical sciences; Middle Aged; N-Methylaspartate - pharmacology; Neurology; Neurotoxins - pharmacology; Okadaic Acid - pharmacology; Precipitin Tests - methods; Proto-Oncogene Proteins c-bcl-2 - metabolism; Receptors, Cytoplasmic and Nuclear - drug effects; Receptors, Cytoplasmic and Nuclear - metabolism; Spectrin - drug effects; Spectrin - metabolism; Tacrolimus - analogs & derivatives; Tacrolimus - therapeutic use; Vascular diseases and vascular malformations of the nervous system; Bcl-2; CN-A; hypoxia; aglycia; CTX; i.p; calcineurin; ER; HIP; ischemia; spectrin-120 kDa; HEPES; IP3-R; NMDA; Human; Oxygen; Nervous system diseases; Toxicity; Calcineurin; Central nervous system; Cardiovascular disease; Environmental factor; Cerebral disorder; Vascular disease; Ischemia; Excitotoxicity; Central nervous system disease; Hypoxia; Cerebrovascular disease; Brain (vertebrata)
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/S0306-4522(02)00934-X

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.