Protein-protein interactions at the NMDA receptor complex: From synaptic retention to synaptonuclear protein messengers

N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels that support essential functions throughout the brain. NMDARs are tetramers composed of the GluN1 subunit in complex with GluN2- and GluN3-type regulatory subunits, resulting in the formation of various receptor subtypes throughout the central nervous system (CNS), characterised by different kinetics, biophysical and pharmacological properties, and the abilities to interact with specific partners at dendritic spines. NMDARs are expressed at high levels, are widely distributed throughout the brain, and are involved in several physiological and pathological conditions. Here, we will focus on the GluN2A- and GluN2B-containing NMDARs found at excitatory synapses and their interactions with plasticity-relevant proteins, such as the postsynaptic density family of membrane-associated guanylate kinases (PSD-MAGUKs), Ca2+/calmodulin-dependent kinase II (CaMKII) and synaptonuclear protein messengers. The dynamic interactions between NMDAR subunits and various proteins regulating synaptic receptor retention and synaptonuclear signalling mediated by protein messengers suggest that the NMDAR serves as a key molecular player that coordinates synaptic activity and cell-wide events that require gene transcription. Importantly, protein-protein interactions at the NMDAR complex can also contribute to synaptic dysfunction in several brain disorders. Therefore, the modulation of the molecular composition of the NMDAR complex might represent a novel pharmacological approach for the treatment of certain disease states.