NMDA receptor (NMDAR) mini-review

Overview

NMDA receptors (NMDARs) are voltage-dependent and ligand-gated ionotropic glutamate receptors that in addition to glutamate, require co-activation with glycine or D-serine for efficient activation [1].

NMDARs are modulated by various compounds and act as non-specific cation channels for Na⁺ K⁺ and Ca²⁺ [2]. Mg²⁺ blocks NMDARs in a voltage-dependent manner when the cell is polarised, while Zn²⁺ blocks the channel in a non-competitive voltage-independent manner [3].

When the receptor opens, an influx of Ca²⁺ occurs - this is essential in processes such as synaptic plasticity which is an important mechanism in learning and memory. NMDARs mediate synaptic plasticity via long-term potentiation (LTP) and long-term depression (LTD) [4] which require Ca²⁺ influx to activate signalling cascades associated with AMPA receptor expression at the synapse [5].

Structure of NMDA receptors

NMDA receptor structure showing binding sites NMDA receptors are heterotetrameric and are composed of GluN1, GluN2 (A-D) and GluN3 (A and B) subunits (Fig 1). Alternative splicing can generate eight isoforms of GluN1 with differing pharmacological properties. Various splice variants of GluN2B, 2C, 2D and GluN3A have also been reported.

For activation of NMDA receptors containing GluN1 and GluN2, two agonists need to bind: glutamate binds to the S1 and S2 regions of the GluN2 subunit and glycine to the S1 and S2 regions of the GluN1 subunit (see figure 1). The GluN2B subunit also possesses a binding site for polyamines which are regulatory molecules that modulate the functioning of the NMDA receptor.

The minimal requirement for functional NMDA receptors in vitro is a di-heteromeric assembly of GluN1 and at least one GluN2 subunit variant. However, more complex tri-heteromeric assemblies, incorporating multiple subtypes of GluN2 subunit, or GluN3 subunits, can be generated in vitro and occur in vivo.

There are many proteins associated with NMDA receptors with important roles in transport of the receptor and structural roles tethering other proteins. Read about some of the major NMDA associated proteins here.

Function of NMDA receptors

The NMDA receptor functions as a modulator of synaptic response and a co-incidence detector. At resting membrane potentials NMDA receptors are inactive. This is due to a voltage-dependent block of the channel pore by magnesium ions, preventing ions flowing through it. Once the channel inhibition is released, by for example, sustained activation of AMPA receptors that depolarise the post-synaptic cell, the NMDA receptor can be activated. This activation leads to a calcium influx into the post-synaptic cells that can initiate a wide range of signalling cascades for example:

activation of CaMKII and phosphorylation of the GluA2 AMPA receptor subunit resulting in LTP (HFS)
activation of PICK1 to drive the PKC-dependent synaptic insertion of AMPA receptors during LTP
activation of hippocalcin, a Ca2+-binding protein that recruits AP2 to the GluA2 AMPA receptor subunit prior to internalisation during LTD (LFS)
activation of PI3K/Akt/GSK3 to modulate LTP

Pharmacology of NMDA receptors

Following the work by Watkins and colleagues showing that prototypic agonist NMDA selectively activates the NMDAR, there has been a great deal of interest in identifying NMDAR compounds. A variety of agonists, antagonists, blockers and modulators have been found for the NMDAR’s glutamate and glycine binding sites as well as the ion channel pore and allosteric sites.

This has helped the discovery that the NMDAR plays an important role in many physiological processes such as synaptic plasticity and transmission, learning and memory as well as in pathophysiological conditions such as Parkinson’s, Huntington’s, schizophrenia and stroke [6].

NMDA receptor competitive antagonists

Acting at the glutamate binding site, D-AP5 is a commonly used NMDA receptor antagonist, It shows a slight preference for GluN2A andGluN2B containing NMDA receptor complexes, with a 5-fold lower Ki value for GluN1/2A over GluN1/2D complexes. Subunit selective antagonists include Ro 04-5595 (GluN2B selective), and UBP141 (GluN2D selective).

NMDA receptor channel blockers

NMDA receptor channel blockers act by binding to the pore of the NMDA receptor channel and are therefore non-competitive antagonists. MK-801 is a commonly used, high affinity non competitive antagonist.

NMDA receptor polyamine site antagonists

Polyamines modulate NMDA receptor function and bind to a site on the GluN2B subunit. Ro 8-4304 is an example of a GluN2B antagonist.

Glycine co-agonist site (S1S2 domain of GluN1)

Glycine	Inhibitory neurotransmitter, NMDA receptor co-agonist
D-Serine	NMDA receptor co-agonist
Cycloserine	GluN2B subunit selective NMDA receptor partial agonist
(R)-HA-966	NMDA receptor glycine site antagonist / partial agonist
CNQX	Potent, competitive AMPA / kainate receptor antagonist. Disodium salt.
DNQX	Selective, competitive AMPA / kainate receptor antagonist
L-689,560	Potent, selective glycine site NMDA receptor antagonist
MDL-105,519	Potent, selective glycine site NMDA receptor antagonist

Glutamate binding site (S1S2 domain of GluN2)

NMDA	Prototypic NMDA receptor agonist
D-AP5	Selective, competitive NMDA receptor antagonist
(R,S)-CPP	Potent NMDA receptor antagonist
D-CPPene	Potent, competitive NMDA receptor antagonist
NVP AAM-077	Potent, competitive NMDA receptor antagonist
UBP141	GluN2D subunit selective NMDA receptor antagonist
UBP145	GluN2C/2D preferring antagonist

Channel blockers

Ketamine	Non-competitive NMDA antagonist
MK-801	Potent, selective, non-competitive NMDA receptor antagonist
Memantine	Non-competitive NMDA receptor antagonist
Dextromethorphan	Low affinity NMDA receptor antagonist
PCP	Non competitive NMDA receptor antagonist

Negative allosteric modulators

Ifenprodil	Non-competitive GluN2B subunit selective NMDA receptor antagonist
Ro-25-26981	GluN2B subunit selective NMDA receptor antagonist
CP-101606	Potent, selective NMDA receptor (NR2B subunit) antagonist
TCN 201	Potent, non-competitive GluN2A subunit selective NMDA receptor antagonist
QNZ46	NR2C/NR2D-selective NMDA receptor non-competitive antagonist
Neu-2000	NR2B-selective, moderate NMDA receptor antagonist

Positive allosteric modulators

Pregnenolone sulphate	NMDA potentiator
CIQ	Non-competitive GluN2B subunit selective NMDA receptor antagonist
UBP710	Potentiates GluN1/GluN2A and GluN1/GluN2B responses

NMDA receptor mini-review references

Laube B, Hirai H, Sturgess M, Betz H, Kuhse J 1997. Molecular determinants of agonist discrimination by NMDA receptor subunits: analysis of the glutamate binding site on the NR2B subunit. Neuron. 18(3):493-503.
Collingridge GL, Olsen RW, Peters J, Spedding M. 2009 A nomenclature for ligand-gated ion channels. Neuropharmacology. 56(1):2-5.
Liu Y, Zhang J. 2000. Recent development in NMDA receptors. Chin Med J (Engl). 113(10):948-56.
Wu LJ, Toyoda H, Zhao MG, Lee YS, Tang J, Ko SW, Jia YH, Shum FW, Zerbinatti CV, Bu G, Wei F, Xu TL, Muglia LJ, Chen ZF, Auberson YP, Kaang BK, Zhuo M. (2005). Upregulation of forebrain NMDA NR2B receptors contributes to behavioral sensitization after inflammation. J Neurosci 25, 11107-11116. Zhuo M (2009) Plasticity of NMDA receptor NR2B subunit in memory and chronic pain. Mol Brain, 2:4 (review).
Loescher C, Malenka RC. 2012 NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD). Cold Spring Harb Perspect Biol.. 1:4(6)
Furukawa H, Singh SK, Mancusso R, Gouaux E. 2005. Subunit arrangement and function in NMDA receptors. Nature. 438(7065):185-92.

NMDA receptor recommended reading

Collingridge GL, Volianskis A, Bannister N, France G, Hanna L, Mercier M, Tidball P, Fang G, Irvine MW, Costa BM, Monaghan DT, Bortolotto ZA, Molnar E, Lodge D, Jane DE (2013) The NMDA receptor as a target for cognitive enhancement. Neuropharmacology 64, 13-26. Leeson, P.D., Iversen, L.L., (1994). The glycine site on the NMDA receptor: structure–activity relationships and therapeutic potential. J. Med. Chem. 37, 4053–4067. Lodge, D., Johnson, K.M., (1990). Noncompetitive excitatory amino acid receptor antagonists. Trends Pharmacol. Sci. 11, 81–86. Monaghan DT, Irvine MW, Costa BM, Fang G, Jane DE (2012) Pharmacological modulation of NMDA receptor activity and the advent of negative and positive allosteric modulators. Neurochemistry International 61, 581-592. Traynelis, S.F., Wollmuth, L.P., McBain, C.J., Menniti, F.S., Vance, K.M., Ogden, K.K., et al., (2010). Glutamate receptor ion channels: structure, regulation, and function. Pharmacol. Rev. 62, 405–496. Evans, R.H., Francis, A.A., Jones, A.W., Smith, D.A.S., Watkins, J.C., (1982). The effects of a series of w-phosphonic a-carboxylic amino acids on electrically evoked and amino acid induced responses in isolated spinal cord preparations. Br. J. Pharmacol. 75, 65–75.

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