Coupling of neuronal 5-HT7 receptors to activation of extracellular-regulated kinase through a protein kinase A-independent pathway that can utilize Epac

Authors

  • Stanley L. Lin,

    1. Department of Psychiatry, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey, USA
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  • Nadine N. Johnson-Farley,

    1. Department of Psychiatry, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey, USA
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  • David R. Lubinsky,

    1. Department of Psychiatry, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey, USA
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  • Daniel S. Cowen

    1. Department of Psychiatry, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey, USA
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Address correspondence and reprint requests to Dr Daniel S. Cowen, Department of Psychiatry, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, 125 Paterson Street, Suite 2200, New Brunswick, NJ 08901, USA. E-mail: cowends@umdnj.edu

Abstract

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 Gs-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 Gs-coupled receptors can proceed through cAMP-dependent pathways that utilize cAMP-GEFs rather than protein kinase A.

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