Diversity in NMDA receptor composition: many regulators, many consequences

Abstract

N-methyl-D-aspartate receptors (NMDARs) are a subtype of ionotropic glutamate receptor, which play a central role in learning, memory, and synaptic development. NMDARs are assembled as tetramers composed of two GluN1 subunits and two GluN2 or GluN3 subunits. Although NMDARs are widely expressed throughout the central nervous system, their number, localization, and subunit composition are strictly regulated and differ in a cell- and synapse-specific manner. The brain area, developmental stage, and level of synaptic activity are some of the factors that regulate NMDARs. Molecular mechanisms that control subunit-specific NMDAR function include developmental regulation of subunit transcription/translation, differential trafficking through the secretory pathway, posttranscriptional modifications such as phosphorylation, and protein-protein interactions. The GluN2A and GluN2B subunits are highly expressed in cortex and hippocampus and confer many of the distinct properties on endogenous NMDARs. Importantly, the synaptic NMDAR subunit composition changes from predominantly GluN2B-containing to GluN2A-containing NMDARs during synaptic maturation and in response to activity and experience. Some of the molecular mechanisms underlying this GluN2 subunit switch have been recently identified. In addition, the balance between synaptic and extrasynaptic NMDARs is altered in several neuronal disorders. Here, the authors summarize the recent advances in the identification of NMDAR subunit-specific regulatory mechanisms.

FIGURE 1. NMDA receptor structure, subunits, and topology

A. NMDA receptors are ionotropic glutamate receptors composed of two GluN1 subunits and two GluN2 or GluN3 subunits. NMDARs are permeable to Ca²⁺, Na⁺ and K⁺. To be activated, they need to bind to glutamate (via GluN2 subunits), glycine (via GluN1) and release the Mg²⁺ blockade by membrane depolarization. B. Seven different NMDAR subunits have been identified: GluN1, GluN2A-D and GluN3A-B. Three regions of GluN1 (N1, C1 and C2), which are subjected to alternative splicing allows for further heterogeneity. C. Each NMDAR subunit is composed of three transmembrane domains (M1, 3 and 4) and one re-entrant loop (M2). Glutamate binds in the pocket created by two extracellular regions (S1-2) present in the N-terminal tail and the loop between M3 and M4, respectively. The C-terminus is cytoplasmic and varies in length between subunits.

FIGURE 2. GluN1 and GluN2 subunits display different spatiotemporal expression

In situ hybridization showing the developmental profile of GluN1 and GluN2 subunits in horizontal rat brain sections. “cx” denotes “cortex”, “st” striatum, “hi” hippocampus, “cb” cerebellum, “t” thalamus, “s” septum and “co” colliculi. Reprinted from Figure 2 in Monyer et al., 1994.

FIGURE 3

The GluN2A and GluN2B C-termini contain distinct regulatory motifs, phosphorylation sites, and protein-protein interaction domains.

FIGURE 4

A. Synaptic maturation results in a switch in synaptic GluN2 subunit composition from predominantly GluN2B-containing to GluN2A-containing NMDARs. Synaptic maturation also results in changing levels of several scaffolding and signaling proteins and an increase in synaptic AMPA receptors. B. Characterization of the developmental GluN2B/A switch by electrophysiological approaches. NMDAR-EPSCs in young animals are more sensitive to ifenprodil inhibition (a selective GluN2B inhibitor) than in older animals. Consistent with slower kinetics for GluN2B vs GluN2A, the decay time in young animals is slower than in adults. Reprinted from Figure 1 in Bellone C and Nicoll RA, 2007.

FIGURE 5. Molecular mechanisms regulating the synaptic GluN2B/A switch

A. Adult animals lacking PSD-95 and PSD-93 show an elevated decay time and sensitivity to ifenprodil inhibition compared to wild-type animals, indicating an impared GluN2 subunit switch. Reprinted from Figure 5 in Elias GM et al., 2008. B. The CK2 inhibitor TBB blocks the GluN2 subunit switch induced by activity in young rat slices. Reprinted from Figure 7 in Sanz-Clemente et al., 2010.