Regulation of the NMDA Receptor by Its Cytoplasmic Domains: (How) is the Tail Wagging the Dog?

Excitatory neurotransmission mediated by N-methyl-d-aspartate receptors (NMDARs) is critical for synapse development, function, and plasticity in the brain. NMDARs are tetra-heteromeric cation-channels that mediate synaptic transmission and plasticity. Extensive human studies show the existence of genetic variants in NMDAR subunits genes (GRIN genes) that are associated with neurodevelopmental and neuropsychiatric disorders, including autism spectrum disorders (ASD), epilepsy (EP), intellectual disability (ID), attention deficit hyperactivity disorder (ADHD), and schizophrenia (SCZ). NMDAR subunits have a unique modular architecture with four semiautonomous domains. Here we focus on the carboxyl terminal domain (CTD), also known as the intracellular C-tail, which varies in length among the glutamate receptor subunits and is the most diverse domain in terms of amino acid sequence. The CTD shows no sequence homology to any known proteins but encodes short docking motifs for intracellular binding proteins and covalent modifications. Our review will discuss the many important functions of the CTD in regulating NMDA membrane and synaptic targeting, stabilization, degradation targeting, allosteric modulation and metabotropic signaling of the receptor. This article is part of the special issue on 'Glutamate Receptors - NMDA Receptors'.