N-methyl-d-aspartate receptor function in neuronal and synaptic development and signaling.

The N-methyl-d-aspartate (NMDA) receptor, among the ionotropic glutamate receptors, are fundamental to integrating and transducing complex signaling in neurons. Glutamate activation of these receptors mediates intracellular signals essential to neuronal and synaptic formation and synaptic plasticity and also contribute to excitotoxic processes in several neurological disorders. The NMDA receptor signaling is mediated by the permeability to Ca2+ and by the large network of signaling and scaffolding proteins associated mostly with the large C-terminal domain of GluN2 subunits. Important studies showed that GluN2 C-terminal interactions differ in accordance with the GluN2 subtype, and this influences the type of signaling that NMDA receptor activity controls. Thus, it is not surprising that mutations in genes that codify for NMDA receptor subunits have been associated with severe neuronal diseases. We will review recent advances and explore outstanding problems in this active area of research.