cAMP-cependent protein kinase inhibits mGluR2 coupling to G-proteins by direct receptor phosphorylation

• Type of Material: Article
• Authors: Herve Schaffhauser, Emory University School of Medicine; Zhaohui Cai, Emory University School of Medicine; Frantisek Hubalek, Emory University School of Medicine; Thomas A. Macek, Emory University School of Medicine; Jan Pohl, Emory University; Thomas Murphy, Emory University; P. Jeffrey Conn, Emory University School of Medicine
• Language: English
• Date: 2000-08-01
• Publisher: Society for Neuroscience
• Publication Version: Final Published Version
• Copyright Statement: Copyright © 2000 Society for Neuroscience
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1523/jneurosci.20-15-05663.2000
• Title of Journal or Parent Work: Journal of Neuroscience
• Volume: 20
• Issue: 15
• Start Page: 5663
• End Page: 5670
• Grant/Funding Information: This work was supported by National Institutes of Health (NIH)–National Institute of Neurological Diseases and Stroke (P.J.C.), NIH–NCRR (J.P.), NIH–National Heart, Lung, and Blood Institute (T.J.M.), and NARSAD grants (H.S., P.J.C.).
• Keywords: desensitization; GROUP-II; HIPPOCAMPAL DENTATE GYRUS; METABOTROPIC GLUTAMATE-RECEPTOR; dentate gyrus; metabotropic; Life Sciences & Biomedicine; CYCLIC-AMP FORMATION; cAMP; C PHOSPHORYLATION; SYNAPTIC TRANSMISSION; Neurosciences & Neurology; LONG-TERM POTENTIATION; glutamate; Science & Technology; IN-VITRO; GTP-BINDING PROTEINS; Neurosciences; CALCIUM OSCILLATIONS; perforant path; phosphorylation
• Research Categories: Biology, Microbiology; Chemistry, Biochemistry

Abstract

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.