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Advanced Neurology NMDA receptors in neuropsychiatric diseases

inhibits the channel [59,63-67] . The physiological function of including lysine-lysine-lysine (KKK), and arginine-
GluN3 NMDARs remains largely unknown. arginine-arginine (RRR) [25,81,82] . The overexpression of
GluN2A and GluN2B in cerebellar granular neurons leads
2.2.2. Gating function of NMDAR to a significant increase in the number of NMDARs and

NMDARs composed of different subunits have different synaptic targeting, probably through the co-assembly
[83]
channel characteristics. The GluN2A and GluN2B- with extra GluN1 . An ER retention sequence (HLFY)
[84]
containing NMDARs have higher conductance, higher has been proposed in the CTD of GluN2B subunit .
Ca permeability, and higher Mg sensitivity compared However, subsequent studies showed that HLFY motif was
2+
2+
to GluN2C and GluN2D-containing NMDARs, which required in the CTD-oriented structure of GluN2B, but its
are regulated by the Ser632 in GluN2A and S633 in might not serve as an ER retention signal . In a recent
[85]
GluN2B site in M3 region . Besides, the channel gating study, the KKK879-881 of GluN2A was proven to be an
[68]
properties are different among NMDARs, including ER retention signal , regulating the surface expression of
[17]
the open probability, deactivation kinetics, and agonist GluN2A-NMDAR.
potency. The open probability of GluN2A-containing GluN2 subunits interact with the proteins of membrane-
NMDARs is higher than that of other GluN2-containing associated guanylate kinases (MAGUK) family, such
NMDARs, and the deactivation of GluN2A-NMDAR is as synaptic associated proteins-102 kDa (SAP102) and
faster too [69,70] . Therefore, the channel of GluN2A closes synaptic associated proteins-97 kDa (SAP97), which is
earlier after activation by glutamate, leading to a fast necessary for NMDAR secretion [86,87] . SAP102 is highly
decay time. Interestingly, GluN1 splicing isoforms also expressed in the hippocampus on the 2 day after birth,
nd
affect NMDAR gating kinetics, that is, the NMDARs with and its PDZ region interaction with GluN2A and GluN2B
GluN1-a deactivates slower than those with GluN1-b [23,24] . subunits of NMDARs makes a difference [88,89] . Moreover,
For the major NMDAR components in the cortex of adult, SAP102 is also widely present in the cytoplasm and ER .
[88]
the GluN1/GluN2A receptors have the faster decay time, In addition, SAP102 interacts with mPins through its SrC-
while the GluN1/GluN2B receptors have higher Ca homology 3 (SH3)/guanylate kinase domain to stabilize
2+
permeability and charge transfer .
[71]
the SAP102-exocyst-NMDAR complex in ER. This process
2.3. NMDARs trafficking plays an important role in promoting NMDAR trafficking
and membrane targeting [86,87] .
NMDAR trafficking is mainly mediated by intracellular
CTD. The difference in CTD sequences of NMDAR NMDARs also have a trafficking pattern that bypasses
subunits leads to subunit-specific regulations on receptor the traditional somatic Golgi network. In this pattern, these
transport, localization and signal transduction [72-74] . The receptors mix directly within the dendrite Golgi . This
[90]
synaptic transmission and escape from the endoplasmic strategy can promote more efficient insertion of NMDARs
reticulum (ER) of NMDARs are regulated by the at the post-synaptic density (PSD). Because they contain
C-terminal splicing of GluN1 , a process that appears to large protein complexes including scaffold molecules,
[25]
[75]
be driven by neuronal activity . The different motives in vesicles produced by this pathway are highly mobile (0.76
the CTDs of GluN2 and GluN3 diversify the trafficking μm/s). Mlin7 binds GluN2B with the motor protein KIF17,
procedures of NMDARs . which promote the long-distance transport of NMDAR-
[76]
containing vesicles on microtubules along dendrites [90-92] .
2.3.1. Receptor biogenesis Studies have shown that KIF17-mediated NMDARs
Typically, NMDARs are first assembled in ER and matured trafficking is critical in long-term potentiation (LTP),
[93]
by glycosylation in the Golgi apparatus before being long-term depression (LTD), learning, and memory .
transported to the plasma membrane through vesicles. Deletion of kif17 leads to NMDAR degradation due to
Cells have strict mechanisms to prevent unassembled enhanced ubiquitination, resulting in partial synaptic
or misfolded NMDARs from being transported to the GluN2A and GluN2B receptors loss. It is interesting that
cell surface . The previous studies indicated that only the interaction of CASK leads SAP97 to preferentially bind
[77]
[94]
in the form of GluN1/GluN2, NMDAR could escape NMDARs . Meanwhile, SAP97 is phosphorylated by
from the ER . Grin1 gene deletion causes the retention Ca /calmodulin-dependent protein kinase II (CaMKII)
2+
[78]
of GluN2 subunit in the ER of hippocampus . Both at two key sites, Ser-39 (in the L27 domain) and Ser-232
[79]
GluN1 and GluN2 subunits contain ER retention signals, (in the PDZ1 domain) [95,96] . Phosphorylation of SAP97
which can be masked by the co-assembly of GluN1 and at Ser-39 leads to translocation of SAP97 from the ER to
GluN2 subunit . For example, the CTD of the GluN1 the post-synaptic compartment, while phosphorylation
[80]
subunit contains positively charged ER retention signals, at Ser-232 disrupts binding of SAP97 to GluN2A. In
Volume 1 Issue 2 (2022) 4 https://doi.org/10.36922/an.v1i2.148