The Shank family of proteins interacts with NMDA receptor and metabotropic glutamate receptor complexes in the postsynaptic density (PSD). Targeted to the PSD by a PDZ-dependent mechanism, Shank promotes the maturation of dendritic spines and the enlargement of spine heads via its ability to recruit Homer to postsynaptic sites. Shank and Homer cooperate to induce accumulation of IP3 receptors in dendritic spines and formation of putative multisynapse spines. In addition, postsynaptic expression of Shank enhances presynaptic function, as measured by increased minifrequency and FM4-64 uptake. These data suggest a central role for the Shank scaffold in the structural and functional organization of the dendritic spine and synaptic junction.

Using a thrombin cleavage assay in cultured hippocampal neurons, we studied the kinetics, regulation and site of AMPA receptor surface delivery. Surface insertion of the GluR1 subunit occurs slowly in basal conditions and is stimulated by NMDA receptor activation and insulin, whereas GluR2 exocytosis is constitutively rapid. Although both subunits ultimately concentrate in synapses, GluR1 and GluR2 show different spatial patterns of surface accumulation, consistent with GluR1 being inserted initially at extrasynaptic sites and GluR2 being inserted more directly at synapses. The spatiotemporal pattern of surface accumulation is determined by the cytoplasmic tails of GluR subunits, and in heteromeric receptors, GluR1 acts dominantly over GluR2. We propose that GluR1 controls the exocytosis and GluR2/3, the recycling and endocytosis of AMPA receptors.