NMDA receptor C-terminal signaling in development, plasticity, and disease

The NMDA subtype of ionotropic glutamate receptor is a sophisticated integrator and transducer of information. NMDAR-mediated signals control diverse processes across the life course, including synaptogenesis and synaptic plasticity, as well as contribute to excitotoxic processes in neurological disorders. At the basic biophysical level, the NMDAR is a coincidence detector, requiring the co-presence of agonist, co-agonist, and membrane depolarization in order to open. However, the NMDAR is not merely a conduit for ions to flow through; it is linked on the cytoplasmic side to a large network of signaling and scaffolding proteins, primarily via the C-terminal domain of NMDAR GluN2 subunits. These physical interactions help to organize the signaling cascades downstream of NMDAR activation. Notably, the NMDAR does not come in a single form: the subunit composition of the NMDAR, particularly the GluN2 subunit subtype (GluN2A–D), influences the biophysical properties of the channel. Moreover, a growing number of studies have illuminated the extent to which GluN2 C-terminal interactions vary according to GluN2 subtype and how this impacts on the processes that NMDAR activity controls. We will review recent advances, controversies, and outstanding questions in this active area of research.