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The Journal of Neuroscience, August 1, 2000, 20(15):5663-5670
cAMP-Dependent Protein Kinase Inhibits mGluR2 Coupling to G-Proteins by Direct Receptor Phosphorylation
Hervé Schaffhauser1, Zhaohui Cai1, Frantisek Hubalek3, Thomas A. Macek2, Jan Pohl4, Thomas J. Murphy1, and P. Jeffrey Conn1, 2 1 Department of Pharmacology, 2 Program in Molecular Therapeutics and Toxicology, 3 Program in Biochemistry, Cell and Developmental Biology, and 4 Microchemical Facilities, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322-3090
One of the primary physiological roles of group II and group III metabotropic glutamate receptors (mGluRs) is to presynaptically reduce synaptic transmission at glutamatergic synapses. Interestingly, previous studies suggest that presynaptic mGluRs are tightly regulated by protein kinases. cAMP analogs and the adenylyl cyclase activator forskolin inhibit the function of presynaptic group II mGluRs in area CA3 of the hippocampus. We now report that forskolin has a similar inhibitory effect on putative mGluR2-mediated responses at the medial perforant path synapse and that this effect of forskolin is blocked by a selective inhibitor of cAMP-dependent protein kinase (PKA). A series of biochemical and molecular studies was used to determine the precise mechanism by which PKA inhibits mGluR2 function. Our studies reveal that PKA directly phosphorylates mGluR2 at a single serine residue (Ser843) on the C-terminal tail region of the receptor. Site-directed mutagenesis combined with biochemical measures of mGluR2 function reveal that phosphorylation of this site inhibits coupling of mGluR2 from GTP-binding proteins
Key words: cAMP; metabotropic; dentate gyrus; perforant path; glutamate; phosphorylation; desensitization
Copyright © 2000 Society for Neuroscience 0270-6474/00/20155663-08$05.00/0
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