title: β-N-oxalyl-L-α,β-diaminopropionic acid regulates mitogen-activated protein kinase signaling by down-regulation of phosphatidylethanolamine-binding protein 1.
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.
authors.affiliation: Department of Biochemistry, Osmania University, Hyderabad, India.
authors.forename: Nalini
authors.initials: N
authors.lastname: Jammulamadaka
authors.forename: Sandeepta
authors.initials: S
authors.lastname: Burgula
authors.forename: Rajesh
authors.initials: R
authors.lastname: Medisetty
authors.forename: Govindan
authors.initials: G
authors.lastname: Ilavazhagan
authors.forename: S L N
authors.initials: SL
authors.lastname: Rao
authors.forename: Surya S
authors.initials: SS
authors.lastname: Singh
mesh_terms: D000599:Amino Acids, Diamino / Q000502:physiology*; D000818:Animals; D045744:Cell Line, Tumor; D002645:Chickens; D015536:Down-Regulation / Q000502:physiology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D049488:Phosphatidylethanolamine Binding Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051381:Rats
chemical_list: D000599:Amino Acids, Diamino; D049488:Phosphatidylethanolamine Binding Protein; C100126:oxalyldiaminopropionic acid; D020928:Mitogen-Activated Protein Kinases