Assembly and cell surface presentation of NMDA receptors

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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
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
15920196 The NR3B subunit does not alter the anesthetic sensitivities of recombinant N-methyl-D-aspartate receptors

Askalany, AR, Yamakura, T, Baba, H, Sakimura, K, Petrenko, AB, Kohno, T

Anesth. Analg. 2005
27558536 Emerging roles of GluN3-containing NMDA receptors in the CNS

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

Nat. Rev. Neurosci. 2016
24607230 Distinct functional and pharmacological properties of Triheteromeric GluN1/GluN2A/GluN2B NMDA receptors

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

Neuron 2014
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
23686171 NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease

Zhou, Q, Paoletti, P, Bellone, C

Nat. Rev. Neurosci. 2013
17514195 NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders

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
12008020 Cloning and characterization of a novel NMDA receptor subunit NR3B: a dominant subunit that reduces calcium permeability

Yuzaki, M, Matsuda, S, Matsuda, K, Kamiya, Y

Brain Res. Mol. Brain Res. 2002
1350383 Heteromeric NMDA receptors: molecular and functional distinction of subtypes

Monyer, H, Schoepfer, R, Lomeli, H, Higuchi, M, Herb, A, Sprengel, R, Burnashev, N, Sakmann, B, Seeburg, PH

Science 1992
9495808 Subunit composition of N-methyl-D-aspartate receptors in the central nervous system that contain the NR2D subunit

Wang, YH, Dunah, AW, Yasuda, RP, Wolfe, BB, Luo, J

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

Horak, M, Wang, YX, Suh, YH, Petralia, RS, Lichnerova, K, Park, SP, Kaniakova, M, Skrenkova, K

J. Biol. Chem. 2015
17997397 Analysis of NR3A receptor subunits in human native NMDA receptors

Samuelsson, EB, Nilsson, A, Muly, EC, Sundström, E, Eriksson, M, Benedikz, E, Bogdanovic, N, Akesson, E

Brain Res. 2007
7903167 Preferential co-assembly of recombinant NMDA receptors composed of three different subunits

Whiting, PJ, le Bourdellès, B, Bain, CJ, Kemp, JA, Wafford, KA

Neuroreport 1993
28303017 NMDA receptors: linking physiological output to biophysical operation

Popescu, GK, Iacobucci, GJ

Nat. Rev. Neurosci. 2017
30479490 Unique Biology and Single-Channel Properties of GluN2A- and GluN2C-Containing Triheteromeric N-Methyl-D-Aspartate Receptors

Bhattacharya, S, Traynelis, SF

J Exp Neurosci 2018
20716669 Glutamate receptor ion channels: structure, regulation, and function

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

Pharmacol. Rev. 2010
8139656 Changing subunit composition of heteromeric NMDA receptors during development of rat cortex

Sheng, M, Jan, YN, Cummings, J, Roldan, LA, Jan, LY

Nature 1994
29242355 The Bioactive Protein-Ligand Conformation of GluN2C-Selective Positive Allosteric Modulators Bound to the NMDA Receptor

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

Mol. Pharmacol. 2018
11823786 Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits

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
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