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Advanced Neurology NMDA receptors in neuropsychiatric diseases

addition, CaMKII-dependent phosphorylation of KIF17 development phase [112-115] . The underlying mechanism
also facilitates unloading of cargo from microtubules . seems to be that the interaction between CTD of GluN2A
[97]
Therefore, successive phosphorylation of SAP97 and with PDZ domain of post-synaptic density protein-95
KIF17 may result in the NMDAR escape from the ER and (PSD-95) is relatively stabler [116,117] . Furthermore, the
promote the insertion of NMDAR at synapses. peptides mimicking GluN2A or GluN2B PDZ binding
motif only causes a decrease in synaptic GluN2A-NMDAR
Recent studies have shown that palmitoylation has
an important regulatory role in NMDARs post-Golgi but not in synaptic GluN2B-NMDAR, indicating that the
PDZ-domain dependent regulation is subunit-related.
trafficking [98,99] . Activity-dependent palmitoylation occurs
in two distinct clusters in the CTD of the GluN2A and Furthermore, the protein phosphorylation of the CTD
GluN2B subunits [99,100] . Palmitoylation of GluN2A and of NMDARs regulates the surface trafficking of receptors.
GluN2B at the second cluster of cysteines leads to retention GluN2B is phosphorylated on Ser-1480 by casein kinase 2
of NMDARs in the Golgi apparatus, resulting in decreased (CK2), which disrupted the interaction with MAGUKs and
surface expression of receptors [100] . Thus, mutation of resulted in decreased synaptic GluN2B expression [117-119] .
the cysteines promotes surface expression of NMDARs, Other factors that regulate the diffusion of NMDARs
although the levels of synaptic NMDARs are not altered [101] . include secreted proteases [120] , extracellular matrix, [121] and
hormones [122,123] .
2.3.2. Receptor exocytosis
2.3.4. Receptor endocytosis
Exocytosis of NMDARs occurs primarily at extrasynaptic
sites [102] , where receptors spread to synapses through The surface receptors are also regulated through receptor
lateral diffusion [103] . In general, a family of soluble internalization. NMDAR endocytosis is dependent
N-ethylmaleimide-sensitive factor attachment protein on development and neuronal activity; the rate of
receptors (SNAREs) proteins mediate the fusion of internalization decreases gradually as neurons mature [124] .
vesicles to the plasma membrane, including target SNARE The CTD of GluN2A and GluN2B contains endocytosis
syntaxin, synaptosome-associated protein (SNAP), and motifs, but GluN2B subunits have relatively higher
vesicular SNARE vesicle-associated membrane protein [104] . endocytosis rates in mature neurons [125] .
Although the role of the SNARE complex in NMDAR The phosphorylation of Y1472 by Fyn kinase induces
exocytosis is critical, the precise role of specific members GluN2B binding with MAGUKs, which stabilizes
of this protein family remains controversial. GluN2B in the synaptic membranes. Reduction
in Y1472 phosphorylation induces the interaction
SNP25 plays an important role in mediating NMDAR
exocytosis in CA3 pyramidal neurons and Xenopus between YEKL1472-1475 endocytic motif and adaptor
protein-2 (AP-2), resulting in increased internalization
oocytes [105,106] . In these studies, botulinum toxin A, which of GluN2B [124,126,127] . On the other hand, Ser-1480
inactivates SNAP25, could block mGluR1- and PKC- phosphorylation by CK2 contributes to increased GluN2B
dependent NMDAR exocytosis. SNAP25 is a substrate internalization [83,128] . Therefore, the phosphorylation/
of PKC; mutation of the Ser-187 phosphate site inhibits dephosphorylation plays an important role in receptor
PKC-mediated NMDAR insertion [107] . Meanwhile, internalization. In GluN2A subunit, the endocytosis is
knockdown of SNAP25 with shRNA also reduces mediated by the di-leucine LL1319-1320 [125] .
NMDAR transmission [108] . Studies have also shown that
another member of the SNAP family, SNAP23, is highly GluN1 subunit also affects the endocytosis of NMDARs
expressed at excitatory synapses and regulates NMDAR containing GluN1/GluN2BΔCTD [129] . Studies have shown
exocytosis [109,110] . Reducing SNAP23 by shRNA knockdown that there are two motifs of internalization in the C0 cassette
or gene deletion impairs surface expression of NMDAR [110] . in GluN1: YKRH838-841 and VWRK858-861. Similar
Taken together, both SNAP23 and SNAP25 are important sequences have been found in GluN2A (YWKL841-844)
in regulating the exocytosis of NMDARs. and GluN2B (YWQF842-845).
GluN3 endocytosis has been relatively poorly studied.
2.3.3. Receptor lateral diffusion
In the GluN3A subunit, PACSIN1 binds to the CTD of
Lateral diffusion of NMDAR on the membrane is along GluN3A through its asparagine-proline-phenylalanine
extrasynapse and synapse [111] . GluN2A-NMDAR and (NPF) domain, thereby regulating the internalization of
GluN2B-NMDAR appear to be differentially located on the GluN3A receptor. Moreover, this regulation mode is
the neuronal surface. GluN2A-NMDAR is preferentially activity-dependent, and destruction of the function of
expressed in the synapse, while the expression of GluN2B- PACSIN1 leads to the accumulation of GluN3A receptors
NMDAR tends to be higher in extrasynapse during at the synapse .
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Volume 1 Issue 2 (2022) 5 https://doi.org/10.36922/an.v1i2.148