Assembly and cell surface presentation of NMDA receptors

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R-HSA-9609736
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Homo sapiens
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N-methyl-D-aspartate receptors (NMDARs) are tetramers that consist of two GluN1 (GRIN1) subunits and two subunits that belong to either the GluN2 (GRIN2) subfamily (GluN2A, GluN2B, GluN2C and GluN2D) or the GluN3 (GRIN3) subfamily (GluN3A and GluN3B). The GluN2/GluN3 subunits in the NMDA tetramer can either be identical, constituting an NMDA di-heteromer (di-heterotetramer), which consists of two subunit types, GluN1 and one of GluN2s/GluN3s, or they can be two different GluN2/GluN3 proteins, constituting an NMDA tri-heteromer (tri-heterotetramer), which consists of three subunit types, GluN1 and two of GluN2s/GluN3s (Monyer et al. 1992, Wafford et al. 1993, Sheng et al. 1994, Dunah et al. 1998, Perez-Otano et al. 2001, Chatterton et al. 2002, Matsuda et al. 2002, Yamakura et al. 2005, Nilsson et al. 2007, Hansen et al. 2014, Kaiser et al. 2018, Bhattacharya et al. 2018, Bhattacharya and Traynelis 2018).
NMDA tetramers assemble in the endoplasmic reticulum and traffic to the plasma membrane as part of transport vesicles (McIlhinney et al. 1998, Perez-Otano et al. 2001). NMDA receptor subunits undergo N-glycosylation, which impacts their trafficking from the endoplasmic reticulum to the plasma membrane. Trafficking efficiency may vary among different subunits of NMDARs (Lichnereva et al. 2015). Mechanistic details, such as glycosyl transferases involved and the type of sugar side chains added, are not known.
As there are eight splicing isoforms of GluN1, four different GluN2 and two different GluN3 proteins, many different combinations of NMDAR subunits are possible, but only a handful of distinct NMDAR receptors have been experimentally confirmed and functionally studied. The composition of NMDARs affects trafficking, spatial (including synaptic) localization, ligand preference, channel conductivity and downstream signal transmission. Prevalent NMDARs differ at different stages of neuronal development, in different regions of the central nervous system, and at different levels of neuronal activity. For review, please refer to Lau and Zukin 2007, Traynelis et al. 2010, Paoletti et al. 2013, Pérez-Otaño et al. 2016, Iacobucci and Popescu 2017.
Literature References
PubMed ID Title Journal Year
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Zhou, Q, Paoletti, P, Bellone, C

Nat. Rev. Neurosci. 2013
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Zukin, RS, Lau, CG

Nat. Rev. Neurosci. 2007
11160393 Assembly with the NR1 subunit is required for surface expression of NR3A-containing NMDA receptors

Sucher, NJ, Lipton, SA, Heinemann, SF, Contractor, A, Perez-Otano, I, Trimmer, JS, Schulteis, CT

J. Neurosci. 2001
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Brain Res. Mol. Brain Res. 2002
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Science 1992
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Mol. Pharmacol. 1998
26045554 Two N-glycosylation Sites in the GluN1 Subunit Are Essential for Releasing N-methyl-d-aspartate (NMDA) Receptors from the Endoplasmic Reticulum

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Brain Res. 2007
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Nat. Rev. Neurosci. 2017
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Bhattacharya, S, Traynelis, SF

J Exp Neurosci 2018
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Myers, SJ, Dingledine, R, Ogden, KK, Wollmuth, LP, Menniti, FS, Hansen, KB, Vance, KM, Yuan, H, Traynelis, SF, McBain, CJ

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Nature 1994
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Burger, PB, Cox, BD, Shaulsky, G, Miller, EJ, Traynelis, SF, Menaldino, DS, Bhattacharya, S, Kaiser, TM, Epplin, MP, Kusumoto, H, Strong, KL, Kell, SA, Liotta, DC

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Lipton, SA, Tong, G, Nakanishi, N, Talantova, M, Awobuluyi, M, Cui, J, Chatterton, JE, Sevarino, KA, Tu, S, Zhang, D, Premkumar, LS, Takahashi, H, Shin, Y

Nature 2002
9849671 Assembly intracellular targeting and cell surface expression of the human N-methyl-D-aspartate receptor subunits NR1a and NR2A in transfected cells

Whiting, PJ, le Bourdellès, B, Tricaud, N, Molnár, E, Streit, P, McIlhinney, RA

Neuropharmacology 1998
24607230 Distinct functional and pharmacological properties of Triheteromeric GluN1/GluN2A/GluN2B NMDA receptors

Ogden, KK, Hansen, KB, Yuan, H, Traynelis, SF

Neuron 2014
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Larsen, RS, Pérez-Otaño, I, Wesseling, JF

Nat. Rev. Neurosci. 2016
15920196 The NR3B subunit does not alter the anesthetic sensitivities of recombinant N-methyl-D-aspartate receptors

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Anesth. Analg. 2005
30056832 Triheteromeric GluN1/GluN2A/GluN2C NMDARs with Unique Single-Channel Properties Are the Dominant Receptor Population in Cerebellar Granule Cells

Bhattacharya, S, DiRaddo, JO, Khatri, A, Hansen, KB, Yi, F, Swanger, SA, Yuan, H, Traynelis, SF

Neuron 2018
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