Cyclic AMP-dependent protein kinase phosphorylates group III metabotropic glutamate receptors and inhibits their function as presynaptic receptors

• Authors: Zhaohui Cai, Emory University School of Medicine; Julie A. Saugstad, Emory University School of Medicine; Scott D. Sorensen, Emory University School of Medicine; Kelly J. Ciombor, Emory University School of Medicine; Congxiao Zhang, Cornell University; Herve Schaffhauser, Emory University School of Medicine; Frantisek Hubalek, Emory University School of Medicine; Jan Pohl, Emory University; Robert M. Duvoisin, Cornell University; P. Jeffrey Conn, Merck Research Laboratories
• Journal Title: Journal of Neurochemistry
• Volume: Volume 78, Number 4
• Publisher: Blackwell Science LTD | 2001-08-01, Pages 756-766
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1046/j.1471-4159.2001.00468.x
• Subjects: Chemistry, Biochemistry; Health Sciences, Pharmacology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Biochemistry & Molecular Biology; Neurosciences; Neurosciences & Neurology; beta-adrenergic; cAMP-dependent protein kinase; mGluR4; mGluR7; mGluR8; phosphorylation; LONG-TERM POTENTIATION; BETA-ADRENERGIC RECEPTORS; HIPPOCAMPAL DENTATE GYRUS; FREELY MOVING RATS; SYNAPTIC TRANSMISSION; PERFORANT PATH; FIBER SYNAPSES; CA1 REGION; LATE-PHASE; CAMP

Abstract

Recent evidence suggests that the functions of presynaptic metabotropic glutamate receptors (mGluRs) are tightly regulated by protein kinases. We previously reported that cAMP-dependent protein kinase (PKA) directly phosphorylates mGluR2 at a single serine residue (Ser843) on the C-terminal tail region of the receptor, and that phosphorylation of this site inhibits coupling of mGluR2 to GTP-binding proteins. This may be the mechanism by which the adenylyl cyclase activator forskolin inhibits presynaptic mGluR2 function at the medial perforant path-dentate gyrus synapse. We now report that PKA also directly phosphorylates several group III mGluRs (mGluR4a, mGluR7a, and mGluR8a), as well as mGluR3 at single conserved serine residues on their C-terminal tails. Furthermore, activation of PKA by forskolin inhibits group III mGluR-mediated responses at glutamatergic synapses in the hippocampus. Interestingly, β-adrenergic receptor activation was found to mimic the inhibitory effect of forskolin on both group II and III mGluRs. These data suggest that a common PKA-dependent mechanism may be involved in regulating the function of multiple presynaptic group II and group III mGluRs. Such regulation is not limited to the pharmacological activation of adenylyl cyclase but can also be elicited by the stimulation of endogenous Gs-coupled receptors, such as β-adrenergic receptors.