MAGUKs are expressed widely throughout the central nervous system. They are the scaffolding proteins closest to the surface of the postsynaptic membrane and they contain multiple PDZ domains.67 The PSD-95 protein is one of the most studied MAGUK scaffolding proteins and is involved in postsynaptic stability as well as excitatory receptor insertion.68 PSD-95 binds to numerous proteins associated with AMPAR and NMDAR complexes. Schnell et al.69 found that interaction between PSD-95 and the AMPA receptor-interacting protein, Stargazin, determines the density of AMPARs at the synapse and through this interaction can regulate synaptic maturation.70 The PSD-95 anchors NMDARs to the postsynaptic membrane and it acts as a signaling scaffold mediating the activation of neuronal nitric oxide synthase (nNOS) by calcium–calmodulin activity following, for example, entry of calcium through NMDAR channels.71 Differences between AMPA and NMDA receptors influence on synaptic events is due, in part, to their respective cytosolic C-terminal binding sites to the PSD-95/ discs large/zona occludens-1 (PDZ) domain-containing scaffolding proteins.72–74 The PDZ domain’s function is to regulate protein–protein interactions by binding to the C-terminus of each respective target protein; thus, highlighting its crucial role in neuroplasticity, dendritic growth, and dendritic arborization.68,75
