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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.
Peavy1, 2,
Mike S. S.
Chang3,
Elaine
Sanders-Bush3, and
P. Jeffrey
Conn1, 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 Gq-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 C 1, 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
Gq 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; Gq/11; Src family
tyrosine kinases
Copyright © 2001 Society for Neuroscience 0270-6474/01/21249619-10$05.00/0
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