Abstract
Regulation of neuronal N-methyl-d-aspartate receptors (NMDARs) by protein kinases is critical in synaptic transmission. However, the molecular mechanisms underlying protein kinase C (PKC) potentiation of NMDARs are uncertain. Here we demonstrate that PKC increases NMDA channel opening rate and delivers new NMDA channels to the plasma membrane through regulated exocytosis. PKC induced a rapid delivery of functional NMDARs to the cell surface and increased surface NR1 immunofluorescence in Xenopus oocytes expressing NMDARs. PKC potentiation was inhibited by botulinum neurotoxin A and a dominant negative mutant of soluble NSF-associated protein (SNAP-25), suggesting that receptor trafficking occurs via SNARE-dependent exocytosis. In neurons, PKC induced a rapid delivery of functional NMDARs, assessed by electrophysiology, and an increase in NMDAR clusters on the surface of dendrites and dendritic spines, as indicated by immunofluorescence. Thus, PKC regulates NMDAR channel gating and trafficking in recombinant systems and in neurons, mechanisms that may be relevant to synaptic plasticity.
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Acknowledgements
The authors thank G. Bassell and D. Faber for their helpful comments on the manuscript and A.P. Wang and M. Martinez for technical support. We acknowledge the Analytical Imaging Facility of the Albert Einstein College of Medicine (M. Cammer, Director). This work was supported by NIH grants NS 20752 and NS 31282 (to R.S.Z.) and NS 07512 (to M.V.L.B.). M.V.L.B. is the Sylvia and Robert S. Olnick Professor of Neuroscience.
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Lan, Jy., Skeberdis, V., Jover, T. et al. Protein kinase C modulates NMDA receptor trafficking and gating. Nat Neurosci 4, 382–390 (2001). https://doi.org/10.1038/86028
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DOI: https://doi.org/10.1038/86028
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