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.

The GRIN genes encoding N-methyl-D-aspartate receptor (NMDAR) subunits are remarkably intolerant to variation. Many pathogenic NMDAR variants result in their protein misfolding, inefficient assembly, reduced surface expression, and impaired functionality at the plasma membrane, causing neurological disorders including epilepsy and intellectual disability. Here, we concentrate on the proteostasis maintenance of NMDARs containing epilepsy-associated variations in the GluN2A (or NR2A) subunit, including M705V and A727T. We showed that these two variants are targeted to the proteasome for degradation and have reduced functional surface expression. We demonstrated that the application of BIX, a known small molecule activator of an HSP70 family chaperone BiP (Binding immunoglobulin Protein) in the endoplasmic reticulum (ER), significantly increases total and surface protein levels, and thus the function of the M705V and A727T variants in HEK293T cells. Mechanistic studies revealed that BIX promotes folding, inhibits degradation, and enhances anterograde trafficking of the M705V variant by modest activation of the IRE1 pathway of the unfolded protein response. Our results showed that adapting the ER proteostasis network restores the folding, trafficking, and function of pathogenic NMDAR variants, representing a potential treatment for neurological disorders resulting from NMDAR dysfunction.