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The Journal of Neuroscience, December 15, 2001, 21(24):9619-9628

Metabotropic Glutamate Receptor 5-Induced Phosphorylation of Extracellular Signal-Regulated Kinase in Astrocytes Depends on Transactivation of the Epidermal Growth Factor Receptor

Richard D. Peavy^{1, 2}, Mike S. S. Chang³, Elaine Sanders-Bush³, and P. Jeffrey Conn^{1, 4}

¹ Department of Pharmacology, Emory University School of Medicine and ² Graduate Program in Molecular and Systems Pharmacology, Graduate Division of Biological and Biomedical Sciences, Emory University, Atlanta, Georgia 30322, ³ Department of Pharmacology and Center for Molecular Neuroscience, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, and ⁴ Department of Neuroscience, Merck Research Laboratories, West Point, Pennsylvania 19485-0004

G-protein-coupled receptors (GPCRs) induce the phosphorylation of mitogen-activated protein (MAP) kinase by actions on any of a number of signal transduction systems. Previous studies have revealed that activation of the G_q-coupled metabotropic glutamate receptor 5 (mGluR5) induces phosphorylation of the MAP kinase extracellular signal-regulated kinase 2 (ERK2) in cultured rat cortical astrocytes. We performed a series of studies to determine the mechanisms underlying mGluR5-induced phosphorylation of MAP kinase in these cells. Interestingly, our studies suggest that mGluR5-mediated ERK2 phosphorylation is dependent on the activation of G_q but is not mediated by the activation of phospholipase C1, activation of protein kinase C, or increases in intracellular calcium. Studies with peptide inhibitors suggest that this response is not dependent on G subunits. However, the activation of ERK2 was dependent on activation of the epidermal growth factor (EGF) receptor and activation of a Src family tyrosine kinase. Furthermore, activation of mGluR5 induced an association of this receptor and the EGF receptor, suggesting the formation of a signaling complex involved in the activation of ERK2. These data suggest that mGluR5 increases ERK2 phosphorylation in astrocytes by a novel mechanism involving the activation of G_q and both receptor and nonreceptor tyrosine kinases but that is independent of the activation of phospholipase C1.

Key words: metabotropic glutamate receptor 5; extracellular signal-regulated kinase 2; epidermal growth factor receptor transactivation; astrocytes; G_q/11; Src family tyrosine kinases

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21249619-10$05.00/0

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