title: The MAPK pathway is required for depolarization-induced "promiscuous" immediate-early gene expression but not for depolarization-restricted immediate-early gene expression in neurons.
abstract: Depolarization, growth factors, neurotrophins, and other stimuli induce expression of immediate early genes (IEGs) in neurons. We identified a subset of IEGs, IPD-IEGs, which are induced preferentially by depolarization, but not by neurotrophins or growth factors, in PC12 cells. The "promiscuous" IEGs Egr1 and c-fos, induced by growth factors and neurotrophins, in addition to depolarization, require activation of the MAP kinase signaling pathway for induction in response to KCl depolarization in PC12 cells; MEK1/2 inhibitors block KCl-induced Egr1 and c-fos expression. In contrast, MEK1/2 inhibition has no effect on KCl-induced expression of the known IPD-IEGs in PC12 cells. Additional "candidate" IDP-IEGs were identified by a microarray comparison of genes induced by KCl in the presence vs. the absence of an MEK1/2 inhibitor in PC12 cells. Northern blot analyses demonstrated that representative newly identified candidate IPD-IEGs, as with the known IPD-IEGs, are also induced by a MAP kinase- independent pathway in response to depolarization, both in PC12 cells and in rat primary cortical neurons. Nerve growth factor and epidermal growth factor are unable to induce the expression of the Crem/Icer, Nur77, Nor1, Rgs2, Dusp1 (Mkp1), and Dscr1 genes in PC12 cells, validating their identification as IPD-IEGs. Inhibiting calcium/calmodulin-dependent kinase II (CaMKII), calcineurin, or protein kinase A (PKA) activity prevents KCl-induced IPD-IEG mRNA accumulation, suggesting that the IPD-IEG genes are induced by depolarization in neurons via a combination of calcineurin/PKA- and CaMKII-dependent pathways.
authors.affiliation: Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Hidevaldo B
authors.initials: HB
authors.lastname: Machado
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Vician
authors.forename: Harvey R
authors.initials: HR
authors.lastname: Herschman
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D019703:Calcineurin / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D051766:Early Growth Response Protein 1 / Q000235:genetics*; D004594:Electrophysiology; D015870:Gene Expression / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008934:Mitogens / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D016716:PC12 Cells / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics*; D051381:Rats; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000502:physiology
chemical_list: D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D008934:Mitogens; D009414:Nerve Growth Factors; D016760:Proto-Oncogene Proteins c-fos; D017868:Cyclic AMP-Dependent Protein Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D020928:Mitogen-Activated Protein Kinases; D019703:Calcineurin