The differences between GluN2A and GluN2B signaling in the brain

Abstract

The N-methyl-d-aspartate (NMDA) receptor, a typical ionotropic glutamate receptor, is a crucial protein for maintaining brain function. GluN2A and GluN2B are the main types of NMDA receptor subunit in the adult forebrain. Studies have demonstrated that they play different roles in a number of pathophysiological processes. Although the underlying mechanism for this has not been clarified, the most fundamental reason may be the differences between the signaling pathways associated with GluN2A and GluN2B. With the aim of elucidating the reasons behind the diverse roles of these two subunits, we described the signaling differences between GluN2A and GluN2B from the aspects of C-terminus-associated molecules, effects on typical downstream signaling proteins, and metabotropic signaling. Because there are several factors interfering with the determination of subunit-specific signaling, there is still a long way to go toward clarifying the signaling differences between these two subunits. Developing better pharmacology tools, such as highly selective antagonists for triheteromeric GluN2A- and GluN2B-containing NMDA receptors, and establishing new molecular biological methods, for example, engineering photoswitchable NMDA receptors, may be useful for clarifying the signaling differences between GluN2A and GluN2B.

Synaptic GluN2A-Containing NMDA Receptors: From Physiology to Pathological Synaptic Plasticity

“…The long CTD of GluN2 subunits displays the lowest homology among GluN2 isoforms, as well as various length and binding partners [25,32,54]. GluN2 CTDs are necessary for receptor surface dynamics and activation of specific metabotropic signaling [32,55]. Protein-protein interactions at the GluN2A CTD are involved in the lower mobility of GluN2A-containing NMDARs at synapses compared to GluN2B-containing ones [25] (see below) [55].…”

“…GluN2 CTDs are necessary for receptor surface dynamics and activation of specific metabotropic signaling [32,55]. Protein-protein interactions at the GluN2A CTD are involved in the lower mobility of GluN2A-containing NMDARs at synapses compared to GluN2B-containing ones [25] (see below) [55]. GluN2 CTD as well as NTD were reported to affect receptor trafficking from the ER, indicating a complex modulation of the receptor delivery to target regions [56].…”

“…Extracellular regulated kinase (ERK) is involved in Mitogen-Activated Protein Kinase (MAPK) downstream signaling and a synapse-to-nucleus communication, which still needs to be clarified. Both GluN2A-and GluN2B-containing NMDAR can be found upstream of ERK activation, suggesting ERK as a promiscuous signaling mediator [55]. ERK was shown to be activated by only a subset of dendritic spines modulating CREB and Elk-1 activity [78].…”

A Review of Molecular Imaging of Glutamate Receptors

“…These properties differ with respect to Mg 2+ block and cation conductance, as well as the kinetics of channel deactivation after prolonged agonism and concerning their intracellular trafficking pathways (for review see Willey et al [ 25 ] and Vieira et al [ 26 ]). The most abundant subunits in adult telencephalon are GluN2A and GluN2B, which seemingly act via distinct signaling pathways (Sun et al [ 27 ]). There is relatively little knowledge about the functional properties of the GluN2C subunit, but its association with GluN1 results in an exclusively glycine-gated receptor.…”

Dysfunction of the corticostriatal pathway in autism spectrum disorders

“…The GluN2B subunit encoded by GRIN2B is a major component of NMDARs that mediates excitatory synaptic transmission in the brain (Sun et al, 2018). Variants and de novo mutations in the human GRIN2B gene have been identified in several neurodevelopmental and psychiatric disorders, including ASD (Hu, Chen, Myers, Yuan, & Traynelis, 2016).…”