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Advanced Neurology NMDA receptors in neuropsychiatric diseases

acids that associate as back-to-side heterodimers between brain [47,48,50] . GluN2B expression remains high in the
GluN1 and GluN2 subunits, adopts a bilobed structure. postnatal period, but only in forebrain regions. GluN2D
Upper R2 lobes of GluN1 and GluN2 subunits interact expression is significantly reduced in adults; remaining
to form a protein-protein interface, while lower R1 lobes GluN2D is mainly expressed in midbrain structures,
connect to the LBD, thus forming a unique dimer-of- including diencephalon and midbrain. The expression of
dimer arrangement [30-35] . Moreover, there are binding sites GluN2A starts from birth and gradually increases over
for allosteric modulators in NTD, including the sites for time, eventually becoming abundant throughout the
extracellular Zn and ifenprodil, the GluN2B-selective CNS. Thus, NMDAR composition of GluN2B changes
2+
antagonist [34,36] ; therefore, the NTD also plays a role in to predominantly GluN2A during development in the
regulating NMDAR gating and function. cerebral cortex and hippocampus . The expression of
[51]
nd
The LBD is formed by the S1 and S2 segments, which GluN2C begins in the 2 week after birth, but is limited to
forms kidney-shaped bilobed structures consisting of an the cerebellum and olfactory bulb. The shift from GluN2B
upper lobe and a lower lobe with the agonist binding sites in to GluN2C occurs in cerebellar granulosa cells during
the gap located between the two lobes . Besides, there are development, resulting in a sharp decrease in the GluN2B
[37]
[48]
three independent contact regions in the LBD heterodimer expression in adulthood .
crystal structures of GluN1 and GluN2A (referred to as sites GluN3A and GluN3B subunits also show different
I, II, and III). Hydrophobic residues of GluN1 and GluN2 expression patterns [52,53] . GluN3A expression is the highest
form sites I and III, and non-polar interactions between in the early postnatal period and then begins to decline
these residues mediate agonist binding domain (ABD) gradually. In contrast, GluN3B expression is increased
heterodimerization . The site II of the ABD contains the during development, with high levels of expression in motor
[37]
binding sites of positive and negative allosteric modulators, neurons in adulthood. GluN2B, GluN2D, and GluN3A
which are highly selective for GluN2A [38-40] . subunits are highly expressed in the early development,
The TMD is formed by M1, M3, and M4 and a suggesting that these subunits play important roles in
[52,53]
reentrant loop (M2). The M2 is in the intracellular of synaptic maturation and synaptogenesis . GluN2A and
the ion channel pore, and the M3 forms the extracellular GluN2B are major subunits in the CNS of adult, especially
region of the channel pore. The residues of pore region are in hippocampus and cortex, suggesting that they play a
[46-48]
highly conserved, which indicates the importance of the role in synaptic function and plasticity .
region. Normally, M3 forms the helical bundle and blocks 2.2. Dynamic characteristics of NMDAR
the pore of channel so that ions cannot pass through the
channel when the M3 helical changes its position [41-43] . 2.2.1. Activation of NMDAR
The agonist binding to the LBD is the first step leading to Glycine and glutamate are required for activation of NMDA
M3 rearrangement [30,31,34,35,44] , followed by multiple short- receptors consisting of GluN1/GluN2 subunits [54-58] . The
lived, intermediate conformations, and eventually channel activation of NMDAR containing of GluN1/GluN3 requires
opening . NMDARs are widely distributed throughout only glycine [53,59] . In the nervous system, glycine is naturally
[45]
the CNS, though the expression of NMDAR subunits present in the extracellular environment (4.2 ± 1.6 μM of
varies in different brain regions and developmental stages. glycine in cerebrospinal fluid) . Other molecules can
[60]
Consistent with a broad CNS distribution, the expression of also activate GluN1/GluN2 receptors as coagonists, such
GluN1 subunits generally begins from embryonic E14 and as D-Serine, L-Serine, D-alanine, and L-alanine. In recent
continues into adulthood [46-48] . Among the GluN1 splicing years, D-Serine has been proposed as the main coagonist
isoforms, GluN1-2 is widely distributed. The GluN1-1 and of synaptic NMDARs, while glycine is the main coagonist
GluN1-4 expression distribution is complementary; the of NMDARs at extrasynapse . Glutamate, the excitatory
[61]
former is distributed in more rostral regions (including neurotransmitter in the CNS, is the native agonist of
cerebral cortex and hippocampus). GluN1-a and GluN1-b GluN1/GluN2 NMDARs. Glutamate (L-glutamic acid or
subtypes have largely overlapped expression patterns, but D-glutamic acid) can activate NMDARs by binding to the
their relative abundance varies from region to region. It LBD of GluN2 subunit. NMDA, N-methyl-L-aspartic acid,
is noteworthy that GluN1-a is expressed in all principal D-aspartic acid, and L-aspartic acid are also the agonists of
neurons in the hippocampus, while GluN1-b is mainly NMDARs .
[62]
confined to the CA3 layer .
[49]
Unlike the conventional NMDARs, glycine binding
Expression of the GluN2 subunit varies in different brain to the GluN1/GluN3 receptor only produces a small
regions during development. In rodents, the GluN2B and excitatory current. Indeed, glycine binding to GluN3
GluN2D subunits are highly expressed in the embryonic activates GluN1/GluN3 receptors, but binding to GluN1

Volume 1 Issue 2 (2022) 3 https://doi.org/10.36922/an.v1i2.148