Trends in Neurosciences
Receptor compartmentalization and trafficking at glutamate synapses: a developmental proposal
Section snippets
Synaptic and extrasynaptic NMDA receptors
Molecular, immunocytochemical and functional data suggest that NR2A, NR2B and NR1 subunits exist in vivo at synaptic sites as diheteromers (e.g. NR1–NR2A or NR1–NR2B) and triheteromers (e.g. NR1–NR2A–NR2B) 1, 2, 3. However, functional extrasynaptic NMDA receptors also exist 4, 5, 6, 7, 8, 9, 10. Like synaptic NMDA receptors, extrasynaptic NMDA receptors can be activated by synaptically released glutamate 11, 12, 13. Insights into the potential importance of extrasynaptic NMDA receptors in vivo
Different MAGUKs show preferences for binding to particular NMDA receptor subunits
The hypothesis that the PSD95 family of MAGUKs compartmentalizes and controls the distribution of vertebrate ionotropic glutamate receptors was advanced in 1992 with the isolation of a 95 kDa protein from the postsynaptic density [17]. Since then, the literature on associations and possible functions of the PSD95 family of molecules has grown exponentially [3]. In addition to binding NMDA receptor heteromers via the C-terminal tails of NR2 subunits 18, 19, 20, members of the PSD95 family bind K+
NMDA receptor currents and synaptic change
Biophysical analyses of the effects of NR2 subunit changes on NMDA receptor channel function indicate that heteromers containing NR2B subunits produce channels with longer open times and longer-lasting series of opening and closing, than do heteromers containing NR2A subunits. Long-open-time channels sum to produce whole cell NMDA receptor currents with longer decay times 1, 2, 33, 34. In association with increased NR2A subunit expression, whole-cell currents driven by NMDA receptors in young
A model for regulation of synaptic plasticity by two MAGUK complexes
These analyses of glutamate receptor regulation in the colliculus and visual cortex, together with the data regarding MAGUKs, suggest that different NMDA receptor scaffolding and signaling complexes effect the trafficking and synaptic localization of NR2A-rich and NR2B-rich NMDA receptors. The data also suggest that with increased retinal activity, PSD95 is inserted into the center of the postsynaptic density and displaces the NR2B–SAP102 complexes, which were initially located at the
Acknowledgements
Work in our laboratories is supported by the National Institute of Neurological Disorders and Stroke grant R01NS3290 (to M.C-P.), the National Eye Institute grants R01EY014074 and R03EYO14420 (to M.C-P.) and The Pierre L. de Bourknecht Amyotrophic Lateral Sclerosis Research Fund (to B.Z.). We would like to thank Drs Cull-Candy and Diamond for kindly providing figures for Box 1.
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