Involvement of NMDA receptors and a p21Ras-like guanosine triphosphatase in the constitutive activation of nuclear factor-kappa-B in cortical neurons.
The transcription factor nuclear factor-kappa-B (NF-kappaB) is now recognised as a key mediator of physiological and pathological plasticity in the central nervous system (CNS), and ionotropic glutamate receptor stimulation potently triggers NF-kappaB activation. This study was designed to identify the mechanisms responsible for the high basal levels of activated NF-kappaB present in neurons in the cerebral cortex. In cultured cortical neurons, the basal levels of activated NF-kappaB were reduced by the glutamate receptor antagonists MK801 and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), but were not affected by exposure to a mitogen-activated protein (MAP) kinase kinase (MEK) inhibitor, a p38 MAP kinase inhibitor or a cyclic guanosine monophosphate (cGMP)-dependent protein kinase inhibitor. However, activated NF-kappaB levels were reduced by a guanylate cyclase inhibitor, the Src-family tyrosine kinase inhibitor PP1, or the farnesyl transferase inhibitors manumycin and farnesyl transferase (Ftase) inhibitor 1. There was no additive effect when MK801 was applied together with manumycin. These results suggest that the basal levels of activated NF-kappaB in cortical neurons are maintained partially by synaptic activity involving N-methyl- D-aspartate (NMDA) and AMPA/kainate glutamate receptors, coupled to activation of an Src-family tyrosine kinase and a p21(Ras)-like guanosine triphosphatase (GTPase) in a cGMP-dependent manner. The results are intriguing in the light of the recent identification of a synaptic p21(Ras) activator stimulated by cGMP.
Burr
P B
PB
Division of Neuroscience and Biomedical Systems, Institute of Biomedical and Life Sciences, West Medical Building, University of Glasgow, Glasgow G12 8QQ, UK.
Morris
B J
BJ
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology; D015536:Down-Regulation; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D020558:GTP Phosphohydrolases / Q000145:classification / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D016328:NF-kappa B / Q000145:classification / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D019335:Nitroarginine / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D011090:Polyenes / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D016283:Proto-Oncogene Proteins p21(ras) / Q000737:chemistry; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D051996:Transcription Factor RelA
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D005419:Flavonoids; D007093:Imidazoles; D016328:NF-kappa B; D010069:Oxadiazoles; D011090:Polyenes; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D011810:Quinoxalines; D016194:Receptors, N-Methyl-D-Aspartate; D051996:Transcription Factor RelA; D019335:Nitroarginine; D016291:Dizocilpine Maleate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; D020558:GTP Phosphohydrolases; D016283:Proto-Oncogene Proteins p21(ras); C054474:manumycin; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one