title: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, but not N-methyl-D-aspartate, activates mitogen-activated protein kinase through G-protein beta gamma subunits in rat cortical neurons.
abstract: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor channels play important roles in plasticity, neurotransmission, and neurotoxicity in the central nervous system. AMPA, but not N-methyl-D-aspartate (NMDA), receptor signaling in rat cortical neurons was found to involve a G-protein coupled to a protein kinase cascade. While both NMDA and AMPA activated p42 mitogen-activated protein kinase (MAPK) in neurons, only AMPA-induced MAPK was inhibited by pertussis toxin. AMPA, but not NMDA, caused an association of a G-protein beta subunit with a Ras, Raf kinase, and MAP/ERK kinase (MEK)-1 complex. The evidence indicates that AMPA triggers MAPK activation via a novel mechanism in which G-protein beta gamma dimers released from G alpha bind to a Ras protein complex causing the activation of Ras, Raf kinase, MEK-1, and finally MAPK.
authors.affiliation: Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: J P
authors.initials: JP
authors.lastname: Durkin
mesh_terms: D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism*; D004789:Enzyme Activation; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D005333:Fetus; D019204:GTP-Binding Proteins / Q000378:metabolism*; D048369:MAP Kinase Kinase 1; D046911:Macromolecular Substances; D020929:Mitogen-Activated Protein Kinase Kinases; D016202:N-Methylaspartate / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D037342:Pertussis Toxin; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf; D051381:Rats; D018091:Receptors, AMPA / Q000187:drug effects / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology*; D018631:ras Proteins / Q000378:metabolism
chemical_list: D018690:Excitatory Amino Acid Agonists; D046911:Macromolecular Substances; D011518:Proto-Oncogene Proteins; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D010566:Virulence Factors, Bordetella; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D037342:Pertussis Toxin; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D019204:GTP-Binding Proteins; D018631:ras Proteins