期刊
JOURNAL OF NEUROCHEMISTRY
卷 87, 期 5, 页码 1076-1085出版社
BLACKWELL PUBLISHING LTD
DOI: 10.1046/j.1471-4159.2003.02076.x
关键词
cAmp; EPac; ERK; hippocampal; neurons; PC12 cells; protein kinase A
资金
- NATIONAL INSTITUTE OF MENTAL HEALTH [R01MH060100] Funding Source: NIH RePORTER
- NIMH NIH HHS [MH 60100] Funding Source: Medline
The roles of 3',5'-cyclic adenosine monophosphate (cAMP) and protein kinase A in 5-hydroxytryptamine (5-HT)(7) receptor-mediated activation of extracellular-regulated kinase (ERK) were studied in cultured hippocampal neurons and transfected PC12 cells. Activation of ERK by neuronal G(s)-coupled receptors has been thought to proceed through a protein kinase A-dependent pathway. In fact we identified coupling of 5-HT7 receptors to activation of adenylyl cyclase and protein kinase A. However, no inhibition of agonist-stimulated ERK activation was found when cells were treated with H-89 and KT5720 at concentrations sufficient to completely inhibit activation of protein kinase A. However, activation of ERK was found to be sensitive to the adenylyl cyclase inhibitor 9-(tetrahydrofuryl)-adenine, suggesting a possible role for a cAMP-guanine nucleotide exchange factor (cAMP-GEF). Co-treatment of cells with 8-(4-chlorophenylthio)-2'-O-methyladenosine 3',5'-cyclic monophosphate, a direct activator of the cAMP-GEFs Epac1 and 2, reversed the inhibition of agonist-stimulated ERK activation induced by adenylyl cyclase inhibition. Additionally, over-expression of Epac1 enhanced 5-HT7 receptor-mediated activation of ERK. These results demonstrate that the activation of ERK mediated by neuronal G(s)-coupled receptors can proceed through cAMP-dependent pathways that utilize cAMP-GEFs rather than protein kinase A.
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