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Review
. 2020 Jul;154(2):121-143.
doi: 10.1111/jnc.14970. Epub 2020 Feb 16.

Regulation of NMDA glutamate receptor functions by the GluN2 subunits

Marta Vieira  1 , Xuan Ling Hilary Yong  2 , Katherine W Roche  1 , Victor Anggono  2
Affiliations
Review

Regulation of NMDA glutamate receptor functions by the GluN2 subunits

Marta Vieira et al. J Neurochem. 2020 Jul.

Abstract

The N-methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate receptors that mediate the flux of calcium (Ca2+ ) into the post-synaptic compartment. Ca2+ influx subsequently triggers the activation of various intracellular signalling cascades that underpin multiple forms of synaptic plasticity. Functional NMDARs are assembled as heterotetramers composed of two obligatory GluN1 subunits and two GluN2 or GluN3 subunits. Four different GluN2 subunits (GluN2A-D) are present throughout the central nervous system; however, they are differentially expressed, both developmentally and spatially, in a cell- and synapse-specific manner. Each GluN2 subunit confers NMDARs with distinct ion channel properties and intracellular trafficking pathways. Regulated membrane trafficking of NMDARs is a dynamic process that ultimately determines the number of NMDARs at synapses, and is controlled by subunit-specific interactions with various intracellular regulatory proteins. Here we review recent progress made towards understanding the molecular mechanisms that regulate the trafficking of GluN2-containing NMDARs, focusing on the roles of several key synaptic proteins that interact with NMDARs via their carboxyl termini.

Keywords: NMDA receptors; endocytosis; endosomal recycling; exocytosis; protein-protein interactions; receptor trafficking; synaptic plasticity.

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Conflict of interest statement

Conflicts of interest: none

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Figures

Figure 1.
Figure 1.. Diversity and biophysical properties of GluN2-containing NMDARs.
A. Schematic diagram of the domain structure of the four GluN2 subunits of NMDARs, GluN2A – GluN2D. B. The modular architecture of a single GluN2 subunit comprising four distinct domains: an amino terminal domain (ATD), the ligand binding domain (LBD) that binds to glutamate, three transmembrane regions and a re-entrant loop that form the ion channel pore, as well as a carboxy terminal domain, which is the most divergent among all GluN2 subunits. C. Representative assemblies of GluN2-containing di- or tri-heteromeric NMDARs known to exist in the mammalian central nervous system. D. Schematic diagram depicting relative differences in the properties of di-heteromeric GluN2-containing NMDAR subtypes.
Figure 2.
Figure 2.. Routes of NMDAR trafficking.
NMDARs are assembled in the ER and Golgi apparatus in the soma or in dendritic Golgi outposts. They are subsequently transported along the dendrite via kinesin-dependent vesicular trafficking on microtubule networks prior to their insertion onto the plasma membrane. Via lateral diffusion, surface NMDARs are incorporated into synapses and stabilized by PSD scaffolding proteins. NMDARs are internalized from the plasma membrane by clathrin-mediated endocytosis and trafficked to early endosomes. From early endosomes, receptors can be recycled back to the plasma membrane or can enter the degradation pathway to late endosomes. The trafficking of distinct GluN2 subunits are differentially regulated at multiple levels, including the rate of lateral diffusion, internalization and post-endocytic sorting.
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