Regulation of Synaptic NMDA Receptor Activity by Post-Translational Modifications

NMDA receptors for the neurotransmitter glutamate are widely distributed in the central nervous system, playing important roles in brain development, function and plasticity. Alterations in their activity are also important mediators in neuropsychiatric and neurodegenerative disorders. The different NMDA receptor subunits (GluN1, GluN2A-D and GluN3A, B) share a similar structure and membrane topology, with an intracellular C-terminus tail responsible for the interaction with proteins important for the trafficking of the receptors, and to control their surface distribution and signalling activity. The latter sequence varies among subunits but consistently contains the majority of post-translational modification sites on NMDA receptors. These modifications, including phosphorylation, ubiquitination, and palmitoylation, regulate interactions with intracellular proteins. Differences in the amino acid sequence between NMDA receptor subunits lead to a differential regulation by post-translational modifications. Since NMDA receptors are formed by oligomerization of different subunits, and each subunit is regulated in a specific manner, this creates multiple possibilities for regulation of these receptors, with impact in synaptic function and plasticity. This review addresses the diversity of mechanisms involved in the post-translational modification of NMDA receptor subunits, and their impact on the activity and distribution of the receptors, as well as their function in nerve cells.