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possibility of a phosphorylation-dependent switch in AMPA receptor interaction with PDZ proteins. Phosphorylation-dependent changes in PDZ interactions could regulate the sorting of AMPA receptors during exocytosis and/or endocytosis (63).

A surprising finding was that GluR2 binds to NSF, an ATPase involved in membrane fusion and vesicle trafficking (6466). NSF binding is mediated by a membrane proximal segment of GluR2’s cytoplasmic tail, distinct from the C terminus that binds to GRIP or PICK-1. Surface expression of AMPA receptors is inhibited by peptides that block the GluR-NSF interaction, suggesting that NSF is involved in the insertion or stabilization of AMPA receptors in the postsynaptic membrane (67). The binding of NSF to AMPA receptor GluR2 subunits in particular seems to allude to the dynamic nature of the trafficking and regulation of AMPA receptors. It is possible that the NSFGluR2 interaction is relevant to synaptic plasticity by regulating the vesicle trafficking or protein unfolding of AMPA receptors (reviewed in ref. 68).

Endocytosis of postsynaptic AMPA receptors is likely to be an important means of depressing excitatory transmission (6971). The underlying dynamics and molecular mechanisms are being uncovered. Using immunofluorescence and surface biotinylation assays, a rapid rate of basal AMPA receptor endocytosis in cultured hippocampal neurons, which is further accelerated in response to synaptic activity, ligand binding, and insulin, has been measured (63). AMPA-induced AMPA receptor internalization is mediated in part by depolarization and calcium influx through voltage-dependent calcium channels and in part by a novel ligand-binding mechanism that is independent of receptor activation. The endocytosis of AMPA receptors depends on dynamin, but multiple signaling pathways converge on this final mechanism (63, 72). For instance, insulin- and AMPA-induced AMPA receptor internalization differentially depend on protein phosphatases; furthermore, they require distinct sequence determinants within the cytoplasmic tails of GluR1 and GluR2 subunits. Once internalized AMPA receptors can be sorted to different destinations. AMPA receptors internalized in response to AMPA stimulation enter a recycling endosome system, whereas those internalized in response to insulin diverge into a distinct (possibly degradative) compartment. Thus the molecular mechanisms and intracellular sorting of AMPA receptors are diverse and depend on the internalizing stimulus (63, 72). In contrast to AMPA receptors, NMDA receptors show negligible internalization over the time course of minutes to an hour (63).

Concluding Remarks

From the many recent studies reviewed above, a daunting picture is emerging of the molecular complexity of the postsynaptic specialization of glutamatergic synapses. Glutamate receptors (which are fundamental components of the postsynaptic membrane) use their cytoplasmic domains to interact with a variety of intracellular proteins. The receptor is thus anchored by, and integrated into, a sophisticated protein network that supports the receptor’s postsynaptic actions and that modulates the receptor’s activity. Within individual synapses, different subclasses of neurotransmitter receptors (e.g., AMPA, NMDA, and mGluRs) are segregated by differential protein interactions into distinct molecular environments that correspond to localized signaling microdomains. Examples include the PSD-95-based protein complex, which brings (among other things) calcium-regulated molecules into the sphere of influence of the NMDA receptor-calcium channel. These distinct microdomains are linked together in the overall PSD architecture by scaffold proteins such as Shank lying deep in the PSD. The NMDA receptor/PSD-95 complex can be regarded as a relatively stable core substructure of the PSD, whereas AMPA receptors and their associated proteins are much more dynamically regulated. The differential protein interactions of NMDA receptors and AMPA receptors ultimately will explain the contrasting cell biological behaviors of these two different glutamate receptors.

Obviously, we have only reached a qualitative descriptive phase in the analysis of the molecular organization of the PSD. It will be critical to determine the stoichiometry and geometry of interactions involving glutamate receptors and other proteins, if we are to appreciate the true functional architecture of this postsynaptic organelle. It should be also clear that we have a rather static view of postsynaptic structure. An important future challenge is to uncover the developmental and activity-dependent regulation of the protein interactions that underlie the dynamics of the postsynaptic specialization.

I am an Assistant Investigator of the Howard Hughes Medical Institute. This work is supported by the National Institutes of Health (Grant NS35050).

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