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 ph osphorylated. In CA1 pyramidal neurons of the hippocampus, activators of pr otein kinase C (PKC) as well as the G-protein-coupled receptor ligands musc arine and lysophosphatidic acid enhanced NMDA-evoked currents. Unexpectedly , this effect was blocked by inhibitors of tyrosine kinases, including a Sr c required sequence and an antibody selective for Src itself. In neurons fr om mice lacking c-Src, PKC-dependent upregulation was absent. Thus, G-prote in-coupled receptors can regulate NMDA receptor function indirectly through a PKC-dependent activation of the non-receptor tyrosine kinase (Src) signa ling cascade.