G-protein-coupled receptors act via protein kinase C and Src to regulate NMDA receptors.
The N-methyl-D-aspartate (NMDA) receptor contributes to synaptic plasticity in the central nervous system and is both serine-threonine and tyrosine phosphorylated. In CA1 pyramidal neurons of the hippocampus, activators of protein kinase C (PKC) as well as the G-protein-coupled receptor ligands muscarine and lysophosphatidic acid enhanced NMDA-evoked currents. Unexpectedly, this effect was blocked by inhibitors of tyrosine kinases, including a Src required sequence and an antibody selective for Src itself. In neurons from mice lacking c-Src, PKC-dependent upregulation was absent. Thus, G-protein-coupled receptors can regulate NMDA receptor function indirectly through a PKC-dependent activation of the non-receptor tyrosine kinase (Src) signaling cascade.
Lu
W Y
WY
Department of Physiology, University of Toronto, Canada.
Xiong
Z G
ZG
Lei
S
S
Orser
B A
BA
Dudek
E
E
Browning
M D
MD
MacDonald
J F
JF
D000470:Alkaloids; D000595:Amino Acid Sequence; D000818:Animals; D053119:Benzophenanthridines; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000502:physiology*; D019833:Genistein / Q000494:pharmacology; D007529:Isoflavones / Q000494:pharmacology; D008246:Lysophospholipids / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008845:Microinjections; D008969:Molecular Sequence Data; D009116:Muscarine / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009473:Neuronal Plasticity; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010617:Phenanthridines / Q000494:pharmacology; D010636:Phenols / Q000494:pharmacology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017966:Pyramidal Cells / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D012459:Salicylates / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000737:chemistry / Q000494:pharmacology; D014982:Xenopus laevis; D062368:meta-Aminobenzoates
D000470:Alkaloids; D053119:Benzophenanthridines; D004791:Enzyme Inhibitors; D007529:Isoflavones; D008246:Lysophospholipids; D009419:Nerve Tissue Proteins; D010617:Phenanthridines; D010636:Phenols; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D011976:Receptors, Muscarinic; D016194:Receptors, N-Methyl-D-Aspartate; D012459:Salicylates; D062368:meta-Aminobenzoates; C092428:lavendustin B; C062898:lavendustin A; C004742:daidzein; D009116:Muscarine; D019833:Genistein; C016299:chelerythrine; D016392:Proto-Oncogene Proteins pp60(c-src); D011493:Protein Kinase C; D019204:GTP-Binding Proteins; D013755:Tetradecanoylphorbol Acetate