β‐ N ‐Oxalyl‐l‐α,β‐diaminopropionic acid regulates mitogen‐activated protein kinase signaling by down‐regulation of phosphatidylethanolamine‐binding protein 1

J. Neurochem. (2011) 118 , 176–186. Abstract β‐ N ‐Oxalyl‐ l ‐α,β‐diaminopropionic acid ( l ‐ODAP) an α‐amino‐3‐hydroxy‐5‐ methyl‐4‐isoxazole propionic acid (AMPA) receptor agonist activates protein kinase C in white leghorn chick brain. The current study focuses on the protein kinase C downstream signaling targets associated with l ‐ODAP excitotoxicity in SK‐N‐MC human neuroblastoma cells and white leghorn male chick ( Gallus domesticus ) brain extracts. l ‐ODAP treatment in SK‐N‐MC cells (1.5 mM) and chicks (0.5 mg/g body weight) results in a decreased expression and increased phosphorylation of phosphatidylehthanolamine‐binding protein 1 (PEBP1) up to 4 h which however, returns to normal by 8 h. d ‐ODAP, the non‐toxic enantiomer however, did not affect PEBP1 levels in either chick brain or SK‐N‐MC cells. Decreased PEBP1 expression correlated with subsequent activation of Raf‐1, MEK and ERK signaling components of the mitogen‐activated protein kinase cascade and nuclear translocation of hypoxia inducible factor‐1α (HIF‐1α) in chick brain nuclear extracts and SK‐N‐MC cells. SK‐N‐MC cells over‐expressing PEBP1 inhibited nuclear translocation of HIF‐1α when treated with l ‐ODAP, indicating that down‐regulation of PEBP1 is responsible for HIF‐1α stabilization and nuclear localization. Excitotoxicity of l ‐ODAP may thus be the result of phosphorylation and down‐regulation of PEBP1, a crucial signaling protein regulating diverse signaling cascades. l ‐ODAP induced convulsions and seizures in chicks could be the result of a hypoxic insult to brain.