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The MAPK pathway is required for depolarization‐induced “promiscuous” immediate‐early gene expression but not for depolarization‐restricted immediate‐early gene expression in neurons
Author(s) -
Machado Hidevaldo B.,
Vician Linda J.,
Herschman Harvey R.
Publication year - 2008
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.21529
Subject(s) - depolarization , biology , immediate early gene , microbiology and biotechnology , nerve growth factor ib , nerve growth factor , calcineurin , signal transduction , gene expression , gene , transcription factor , endocrinology , medicine , receptor , biochemistry , transplantation , nuclear receptor
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 i nduced p referentially by d epolarization, 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. © 2007 Wiley‐Liss, Inc.