h-89 and 2-(2-3-dicarboxycyclopropyl)glycine

The cAMP/protein kinase A signaling pathway is negatively modulated by group II metabotropic glutamate receptors (mGluRs), and the cross-talk that occurs between these receptors may modulate learning and memory. To examine the relationship among cAMP/PKA-signaling pathway activity, group II mGluRs, and learning and memory, mice were trained to perform a step-through-type passive avoidance task, and 10 min before each avoidance trial the following drugs were injected intracisternally (i.cist.): vehicle (0.05% dimethylsulfoxide); a specific group II mGluR agonist, DCG-IV (1-50 ng/mouse); a specific group II mGluR antagonist, LY341495 (10-300 ng); a selective inhibitor of cAMP-specific phosphodiesterase, rolipram (100-1000 ng); an activator of adenylyl cyclase, forskolin (25-250 ng); a specific inhibitor of PKA, H-89 (150 or 300 ng) or; an activator of protein kinase C, phorbol 12-myristate 13-acetate (PMA 200 ng). DCG-IV (25 and 50 ng) or LY341495 (150 and 300 ng) reduced the latency in the avoidance task. The reduction of latency by DCG-IV was not observed in mice coinjected with DCG-IV (50 ng) together with rolipram (500 ng) or forskolin (25 ng). Conversely, coinjection of LY341495 with 100 or 1000 ng rolipram, or with 25 or 250 ng forskolin tended to potentiate the LY341495-induced shortening of latency. In addition, the reduction of latency by DCG-IV (50 ng) was not observed in mice coinjected with DCG-IV and PMA together. However, the reduction of latency by LY341495 (300 ng) was potentiated when the drug was coadministered with PMA. These results suggest that changes in the cAMP/PKA-signaling pathway, mediated by group II mGluRs, influence memory in the passive avoidance task, and that both the excessive activation and deactivation of this pathway may induce the impairment of learning and memory.

Topics: Amino Acids; Animals; Anticonvulsants; Avoidance Learning; Colforsin; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclopropanes; Dose-Response Relationship, Drug; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Glycine; Isoquinolines; Male; Memory; Mice; Reaction Time; Receptors, Metabotropic Glutamate; Rolipram; Signal Transduction; Sulfonamides; Tetradecanoylphorbol Acetate; Xanthenes

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

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Adenine; Amino Acid Sequence; Animals; Anticonvulsants; CHO Cells; Cricetinae; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclopropanes; Dentate Gyrus; Enzyme Inhibitors; Excitatory Postsynaptic Potentials; Glutamic Acid; Glycine; GTP-Binding Proteins; Guanosine 5'-O-(3-Thiotriphosphate); Isoquinolines; Molecular Sequence Data; Mutagenesis; Neurons; Perforant Pathway; Phosphorylation; Protein Binding; Rats; Receptors, Metabotropic Glutamate; Serine; Sulfonamides; Transfection