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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 Conn^{1, 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

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20155663-08$05.00/0

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