Abstract
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.
MeSH Terms
Alkaloids
Amino Acid Sequence
Animals
Benzophenanthridines
Cells, Cultured
Enzyme Activation/drug effects
Enzyme Inhibitors/pharmacology
GTP-Binding Proteins/physiology
Genistein/pharmacology
Isoflavones/pharmacology
Lysophospholipids/pharmacology
Mice
Mice, Knockout
Microinjections
Molecular Sequence Data
Muscarine/pharmacology
Nerve Tissue Proteins/physiology
Neuronal Plasticity
Oocytes/drug effects,metabolism
Patch-Clamp Techniques
Phenanthridines/pharmacology
Phenols/pharmacology
Phosphorylation
Protein Kinase C/antagonists & inhibitors,physiology
Protein Processing, Post-Translational
Proto-Oncogene Proteins pp60(c-src)/antagonists & inhibitors,deficiency,genetics,physiology
Pyramidal Cells/drug effects,physiology
Rats
Rats, Wistar
Receptors, Cell Surface/drug effects,physiology
Receptors, G-Protein-Coupled
Receptors, Lysophosphatidic Acid
Receptors, Muscarinic/drug effects,physiology
Receptors, N-Methyl-D-Aspartate/physiology
Salicylates/pharmacology
Signal Transduction/drug effects,physiology
Tetradecanoylphorbol Acetate/chemistry,pharmacology
Xenopus laevis
meta-Aminobenzoates
Chemicals
Alkaloids
Benzophenanthridines
Enzyme Inhibitors
Isoflavones
Lysophospholipids
Nerve Tissue Proteins
Phenanthridines
Phenols
Receptors, Cell Surface
Receptors, G-Protein-Coupled
Receptors, Lysophosphatidic Acid
Receptors, Muscarinic
Receptors, N-Methyl-D-Aspartate
Salicylates
meta-Aminobenzoates
lavendustin B
lavendustin A
daidzein
Muscarine
Genistein
chelerythrine
Proto-Oncogene Proteins pp60(c-src)
Protein Kinase C
GTP-Binding Proteins
Tetradecanoylphorbol Acetate
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Lu W Y
Department of Physiology, University of Toronto, Canada.
Xiong Z G
Lei S
Orser B A
Dudek E
Browning M D
MacDonald J F