cAMP-dependent protein kinase inhibits mGluR2 coupling to G-proteins by direct receptor phosphorylation.
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 (Ser(843)) 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
Schaffhauser
H
H
Department of Pharmacology, Program in Molecular Therapeutics and Toxicology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322-3090, USA.
Cai
Z
Z
Hubalek
F
F
Macek
T A
TA
Pohl
J
J
Murphy
T J
TJ
Conn
P J
PJ
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D003521:Cyclopropanes / Q000494:pharmacology; D018891:Dentate Gyrus / Q000166:cytology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000201:enzymology; D019580:Perforant Pathway / Q000166:cytology; D010766:Phosphorylation; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D013449:Sulfonamides; D014162:Transfection
D000927:Anticonvulsants; D003521:Cyclopropanes; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D018094:Receptors, Metabotropic Glutamate; D013449:Sulfonamides; C108822:metabotropic glutamate receptor 2; C082313:2-(2,3-dicarboxycyclopropyl)glycine; C017759:9-(tetrahydro-2-furyl)-adenine; D015124:8-Bromo Cyclic Adenosine Monophosphate; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D018698:Glutamic Acid; D012694:Serine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019204:GTP-Binding Proteins; D000225:Adenine; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D005998:Glycine