Protein kinase C modulates NMDA receptor trafficking and gating

Regulation of neuronal N-methyl-D-aspartate receptors (NMDARs) by protein k inases is critical in synaptic transmission. However, the molecular mechani sms underlying protein kinase C (PKC) potentiation of NMDARs are uncertain. Here we demonstrate that PKC increases NMDA channel opening rate and deliv ers new NMDA channels to the plasma membrane through regulated exocytosis. PKC induced a rapid delivery of functional NMDARs to the cell surface and i ncreased surface NR1 immunofluorescence in Xenopus oocytes expressing NMDAR s. PKC potentiation was inhibited by botulinum neurotoxin A and a dominant negative mutant of soluble NSF-associated protein (SNAP-25), suggesting tha t receptor trafficking occurs via SNARE-dependent exocytosis. In neurons, P KC induced a rapid delivery of functional NMDARs, assessed by electrophysio logy, and an increase in NMDAR clusters on the surface of dendrites and den dritic spines, as indicated by immunofluorescence. Thus, PKC regulates NMDA R channel gating and trafficking in recombinant systems and in neurons, mec hanisms that may be relevant to synaptic plasticity.