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Advanced Neurology NMDA receptors in neuropsychiatric diseases

Pharmacologically, the ionotropic glutamate receptors is essential to guide the treatments of the neuropsychiatric
are grouped into three types : α-amino-3-hydroxy-5- disorders.
[1]
methyl-4-isoxazole propionic acid (AMPA) receptors In this review, we discuss the molecular properties of
(AMPARs), kainate receptors, and N-methyl-D-aspartic the NMDA receptors and their roles in neuropsychiatric
acid (NMDA) receptors (NMDARs). AMPARs are disorders. We also extend our discussion to the potential
composed of homomeric or heteromeric assembly of therapeutic effects of NMDAR; specifically, it is possible
four subunits: GluA1-4. Kainite receptors are homomeric to reverse the improper synaptic transmission and to
GluK1-3 (GluR5-7 in old nomenclature), or heteromeric further mitigate the clinical symptoms of neuropsychiatric
assembly of GluK1/2/3 with GluK4/5 (used to be KA1/2). disorders by targeting NMDARs.
NMDARs are heterotetramers composed of two subunits
of GluN1, the obligatory subunits, and GluN2A-D or 2. Molecular properties of NMDA receptors
GluN3A-B. Virtually, glutamate receptors play essential
roles in probably every physiological function in the 2.1. NMDARs subunit structure and expression pattern
brain; dysregulation of these receptors causes a variety of NMDARs are composed of seven distinct subunits,
neuropsychiatric disorders. including GluN1 subunit, four distinct GluN2 subunits
(GluN2A, GluN2B, GluN2C, and GluN2D), and two
Neuropsychiatric disorders, including neurodegenerative [1,21,22]
and neurodevelopmental disorders, such as Alzheimer’s GluN3 subunits (GluN3A and GluN3B) . All
NMDARs are heterotetramers, each composed of two
disease (AD) and Autism spectrum disorders (ASD), GluN1 subunits and two identical or different subunits
are severely impair the self-cognition and social of GluN2s or GluN3s [1,21,22] . The different combination
communication of individuals and may also genetically of GluN2/GluN3 subunits also leads to the diversity of
affect their descendants [2-5] . As the growing and aging receptor compositions in the CNS.
population, researching on the neuropsychiatric disorders
is of particular interest to scientists and clinicians. Due to The GluN1 subunit is encoded by a single gene, but
the complexity of these diseases, it is still very challenging due to alternative splicing, it has eight different isoforms
for researchers to understand the underlying mechanisms (GluN1-1a-4a and GluN1-1b-4b). Compared to GluN1-a
of these diseases [6-9] . The rapid development of genetic isoforms, GluN1-b isoforms contain exon 5, leading
and molecular biotechnology provides an avenue for us to to additional extracellular 21 amino acid extensions
explore the pathogenesis of neuropsychiatric disorders [10,11] . (called N1 cassette) that influence the NMDA affinity
With the support from genome-wide association studies and pharmacological properties [23,24] . GluN1-1 to -4 were
and next-generation sequencing technology, the potential derived from the difference of alternative splicing in exon
genetic architecture of human psychiatric diseases could 21 and exon 22, which alter the C-terminal domain (CTD)
[25]
be directly investigated [12-14] . In combination with genetic length and trafficking capacity .
modified mouse, the disease-associated risk genes could All ionotropic glutamate receptor subunits consist
be further confirmed in different psychiatric disorders, of four domains [1,26,27] . A long N-terminal domain
such as SHANK gene that is associated with autistic- (NTD) in the extracellular domain is mainly involved
like behavior and GRIA3 gene that are associated with in subunit assembly and allosteric regulation. A ligand-
[15]
aggressive behavior . As numerous genetic variants have binding domain (LBD) consisting of two discontinuous
[16]
been identified in psychiatric patients, potential molecular fragments (S1 and S2) is the domain for binding
mechanism underlying these diseases could be gradually of glycine (or D-serine) in GluN1 or GluN3 and of
elucidated. glutamate in the GluN2 subunit. The transmembrane
Many gene variants, which may act as the causal domain (TMD) of NMDAR is composed of three
factors for these neuropsychiatric disorders, have been transmembrane regions (M1, M3, and M4) and a
uncovered to affect the neuroplasticity [17,18] . In the central reentrant loop (M2), which form the channel pore for
nervous system (CNS), precise signal transmission is the the influx of ions. The final structure is the intracellular
cornerstone of human physiological processes, and the CTD, the length of which varies a lot and determines
[1]
proper protein structure and function are required to the length difference among NMDAR subunits . CTD
maintain the fine-tune neuronal communication [19,20] . is involved in receptor trafficking, post-synaptic protein
Therefore, numerous efforts have focused on identifying anchoring and protein-protein interactions, as well as
[22,28,29]
new gene variants in neuropsychiatric disorders and many signaling pathways .
investigating the related mechanism. Understanding of The NTD of NMDARs plays a critical role in the
the physiological and pathogenic function of these genes assembly of NMDARs. The NTD, formed by 1–350 amino

Volume 1 Issue 2 (2022) 2 https://doi.org/10.36922/an.v1i2.148