Protein quality control of N-methyl-D-aspartate receptors

Abstract

N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated cation channels that mediate excitatory neurotransmission and are critical for synaptic development and plasticity in the mammalian central nervous system (CNS). Functional NMDARs typically form via the heterotetrameric assembly of GluN1 and GluN2 subunits. Variants within GRIN genes are implicated in various neurodevelopmental and neuropsychiatric disorders. Due to the significance of NMDAR subunit composition for regional and developmental signaling at synapses, properly folded receptors must reach the plasma membrane for their function. This review focuses on the protein quality control of NMDARs. Specifically, we review the quality control mechanisms that ensure receptors are correctly folded and assembled within the endoplasmic reticulum (ER) and trafficked to the plasma membrane. Further, we discuss disease-associated variants that have shown disrupted NMDAR surface expression and function. Finally, we discuss potential targeted pharmacological and therapeutic approaches to ameliorate disease phenotypes by enhancing the expression and surface trafficking of subunits harboring disease-associated variants, thereby increasing their incorporation into functional receptors.

Postsynaptic Proteins at Excitatory Synapses in the Brain—Relationship with Depressive Disorders

“…Observed discrepancies may be explained by the different functional morphology and physiology of NMDARs in other parts of the CNS. As already mentioned above, NMDARs form heterotetramers, most often composed of two GluN1 subunits that bind to two additional subunits: GluN2 (A-D), which binds Glu, or less commonly GluN3 (A-B) with high affinity for glycine [ 180 ]. NMDARs most often consist of GluN1 and GluN2 subunits, particularly GluN2A and GluN2B [ 181 , 182 ].…”

“…Much research to date has focused on diheteromeric NMDARs containing identical GluN2 or GluN3 subunits. However, the triheteromeric NMDAR containing a combination of GluN2 and/or GluN3 subunits has different channel gating kinetics and pharmacology from diheteromeric receptors [ 180 ]. With that in mind, extending protein research on NMDARs with additional subunits and studies showing their coexistence and variety in selected regions of the brain is essential.…”

The effects and mechanism of environmental enrichment on MK-801 induced cognitive impairment in rodents with schizophrenia

“…EE can promote the expression of NMDA receptor in the hippocampus of neonatal rodents treated with MK-801. NMDA receptor in the central nervous system mainly consist of tetramers of GluN1 and GluN2A/GluN2B subunits (Benske et al, 2022 ). MK-801 can down-regulate the expression of the NR1 subunit of the NMDA receptor in the hippocampus, and EE treatment can restore the expression level of NR1.…”

Adapting the endoplasmic reticulum proteostasis rescues epilepsy-associated NMDA receptor variants

“…These NR2A variants lead to impaired signaling at the plasma membrane [10] . Although recent advances in whole genome sequencing have identified an increasing number of pathogenic variants in various subunits of NMDARs, the precise mechanism of how these variants influence receptor surface delivery and function remains poorly understood [11] .…”

“…We focus on proteostasis maintenance of neurotransmitter-gated ion channels, including NMDARs [11,12] . NMDAR subunits are folded and assembled to heterotetramers in the endoplasmic reticulum (ER), a cellular organelle for protein quality control with the assistance of molecular chaperones.…”