In vitro hypoxia and excitotoxicity in human brain induce calcineurin-Bcl-2 interactions.
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.
Erin
N
N
Department of Pharmacology, H078, 500 University Drive, Pennsylvania State University, College of Medicine, Hershey, PA 17033, USA.
Lehman
R A W
RA
Boyer
P J
PJ
Billingsley
M L
ML
D000328:Adult; D015153:Blotting, Western; D019703:Calcineurin / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004792:Enzyme Precursors / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D002534:Hypoxia, Brain / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D066298:In Vitro Techniques; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007608:Kainic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D016202:N-Methylaspartate / Q000494:pharmacology; D009498:Neurotoxins / Q000494:pharmacology*; D019319:Okadaic Acid / Q000494:pharmacology; D011233:Precipitin Tests / Q000379:methods; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000378:metabolism; D013049:Spectrin / Q000187:drug effects / Q000378:metabolism; D016559:Tacrolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use
D015220:Calcium Channels; D004791:Enzyme Inhibitors; D004792:Enzyme Precursors; C506926:ITPR1 protein, human; D007166:Immunosuppressive Agents; D053496:Inositol 1,4,5-Trisphosphate Receptors; D009498:Neurotoxins; D019253:Proto-Oncogene Proteins c-bcl-2; D018160:Receptors, Cytoplasmic and Nuclear; D013049:Spectrin; D019319:Okadaic Acid; D016202:N-Methylaspartate; C058028:immunomycin; D019703:Calcineurin; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; C012301:domoic acid; D007608:Kainic Acid; D016559:Tacrolimus