Domoic acid enhances Bcl-2-calcineurin-inositol-1,4,5-trisphosphate receptor interactions and delayed neuronal death in rat brain slices.
Mechanisms of neuronal death following neuronal damage due to domoic acid are not completely defined. Bcl-2, a survival protein, protects neurons from ischemia and excitotoxin-induced damage. We previously demonstrated that Bcl-2 shuttles calcineurin to its substrates and may regulate calcium release from internal stores during neuronal ischemia. We now confirm that during excitotoxicity induced by domoic acid, calcineurin-Bcl-2 and calcineurin-1,4,5-inositol-trisphosphate receptor (IP3-R) interactions increase. Furthermore, we now show that calcineurin-IP3-R interactions are mediated by Bcl-2 in brain slices following short-term treatment with domoic acid (10 microM). Domoic acid induced late neuronal death and caspase-3-like activity in organotypic cortical and hippocampal cultures. These experiments further define the mechanisms by which neurons respond to excitotoxic insults, and suggest that interactions between calcineurin and its target proteins may influence cellular responses to injury.
Erin
Nuray
N
Department of Pharmacology, College of Medicine, Pennsylvania State University, H078 Hospital, 500 University Drive, Hershey, PA 17033, USA.
Billingsley
Melvin L
ML
D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D019254:Genes, bcl-2 / Q000187:drug effects / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007608:Kainic Acid / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000633:toxicity*; D009467:Neuromuscular Depolarizing Agents / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*
D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D009467:Neuromuscular Depolarizing Agents; D018160:Receptors, Cytoplasmic and Nuclear; D019703:Calcineurin; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; C012301:domoic acid; D007608:Kainic Acid