title: Extracellular signal-regulated kinase 1/2 is required for the induction of group I metabotropic glutamate receptor-mediated epileptiform discharges.
abstract: Transient stimulation of group I metabotropic glutamate receptors (mGluRs) induces persistent prolonged epileptiform discharges in hippocampal slices via a protein synthesis-dependent process. At present, the signaling process underlying the induction of these epileptiform discharges remains unknown. We examined the possible role of extracellular signal-regulated kinases (ERK1 and ERK2) because these kinases can be activated by group I mGluRs, and their activation may regulate gene expression and alter protein synthesis. The group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG; 50 microm) induced activation of ERK1/2 in hippocampal slices. 2-(2-Diamino-3-methoxyphenyl-4H-1-benzopyran-4-one (PD98059) (50 microm) a specific inhibitor of mitogen-activated protein kinase kinase (MEK), suppressed ERK1/2 activation by DHPG. PD98059 or another MEK inhibitor, 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene (10 microm), also prevented the induction of the prolonged epileptiform discharges by DHPG. In the presence of ionotropic glutamate receptor inhibitors and tetrodotoxin (blockers), DHPG-induced epileptiform discharges were suppressed, whereas ERK1/2 activation persisted. Protein kinase C inhibitors (2-[1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl]-3-(1H-indol-3-yl) maleimide, 1 microm; or chelerythrine, 10 microm) did not prevent the generation of DHPG-induced epileptiform discharges, nor did they suppress the activation of ERK1/2 by DHPG in slices pretreated with the blockers. Genistein (30 microm), a broad-spectrum tyrosine kinase inhibitor, suppressed the DHPG-induced epileptiform discharges and the ERK1/2 activation in the presence of blockers. Induction of DHPG-mediated epileptiform discharges was also suppressed by 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-D]pyrimidine (10 microm), an Src-family tyrosine kinase inhibitor. The study shows that group I mGluRs activate ERK1/2 through a tyrosine kinase-dependent process and that this activation of ERK1/2 is necessary for the induction of prolonged epileptiform discharges in the hippocampus.
authors.affiliation: Department of Physiology and Pharmacology, State University of New York Downstate Medical Center, Brooklyn, New York 11203, USA.
authors.forename: Wangfa
authors.initials: W
authors.lastname: Zhao
authors.forename: Riccardo
authors.initials: R
authors.lastname: Bianchi
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.forename: Robert K S
authors.initials: RK
authors.lastname: Wong
mesh_terms: D000200:Action Potentials; D000818:Animals; D002478:Cells, Cultured; D004827:Epilepsy / Q000209:etiology; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D008734:Methoxyhydroxyphenylglycol; D011505:Protein-Tyrosine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C010117:3,4-dihydroxyphenylglycol