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

One of the primary physiological roles of group II and group III metabotrop ic glutamate receptors (mGluRs) is to presynaptically reduce synaptic trans mission at glutamatergic synapses. Interestingly, previous studies suggest that presynaptic mGluRs are tightly regulated by protein kinases. cAMP anal ogs and the adenylyl cyclase activator forskolin inhibit the function of pr esynaptic group II mGluRs in area CA3 of the hippocampus. We now report tha t forskolin has a similar inhibitory effect on putative mGluR2-mediated res ponses at the medial perforant path synapse and that this effect of forskol in is blocked by a selective inhibitor of cAMP-dependent protein kinase (PK A). A series of biochemical and molecular studies was used to determine the precise mechanism by which PKA inhibits mGluR2 function. Our studies revea l that PKA directly phosphorylates mGluR2 at a single serine residue (Ser(8 43)) on the C-terminal tail region of the receptor. Site-directed mutagenes is combined with biochemical measures of mGluR2 function reveal that phosph orylation of this site inhibits coupling of mGluR2 from GTP-binding protein s.