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Review
. 2010 May;91(1):23-37.
doi: 10.1016/j.pneurobio.2010.01.004. Epub 2010 Jan 25.

Influence of the NR3A subunit on NMDA receptor functions

Maile A Henson  1 , Adam C Roberts, Isabel Pérez-Otaño, Benjamin D Philpot
Affiliations
Review

Influence of the NR3A subunit on NMDA receptor functions

Maile A Henson et al. Prog Neurobiol. 2010 May.

Abstract

Various combinations of subunits assemble to form the NMDA-type glutamate receptor (NMDAR), generating diversity in its functions. Here we review roles of the unique NMDAR subunit, NR3A, which acts in a dominant-negative manner to suppress receptor activity. NR3A-containing NMDARs display striking regional and temporal expression specificity, and, unlike most other NMDAR subtypes, they have a low conductance, are only modestly permeable to Ca(2+), and pass current at hyperpolarized potentials in the presence of magnesium. While glutamate activates triheteromeric NMDARs composed of NR1/NR2/NR3A subunits, glycine is sufficient to activate diheteromeric NR1/NR3A-containing receptors. NR3A dysfunction may contribute to neurological disorders involving NMDARs, and the subunit offers an attractive therapeutic target given its distinct pharmacological and structural properties.

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Figures

Figure 1
Figure 1
Schematic diagram of cDNA structures for human and rat NR3A. Both human and rat have NR3A-1 isoforms, also known as NR3A-short (or -s). Rats also have an NR3A-2 isoform, also known as NR3A-long (or -l). Exons 1–9 appear in blue filled boxes (E1-E9). Predicted transmembrane (TM) domains 1–4 are indicated, and region of highest homology is between TM 1 & 4. Lowest homology is found in the C-terminus, which corresponds to the area following TM4. Location of the alternative splice variant (20-amino acid insert) in rodents is denoted in white with an asterisk (*). Percent identity in exon 9 is between NR3A-short sequences, and does not include the 20-amino acid insert found in rat.
Figure 2
Figure 2
Putative transmembrane topology of rat NR3A. Predicted sites are shown for signal peptide (SP), glycosylation (glyc), phosphorylation (PKC, CaMKII, PTK), and protein binding (indicated by dotted lines for PACSIN1/syndapin1, MAP1S, PP2A, plectin, CARP1, and GPS2). Sequence motifs (-CC-, -G-, -YTANLAAV-, -RXR-), transmembrane regions (TM1-TM4) and the extracellular ligand-binding domain/glycine binding pocket (S1-S2) are noted. Predicated kinase phosphorylation sites are indicated by open circles (○). A polyproline motif is indicated by a single black circle (●). CaMKII site predicted for human but not rat is indicated within a square symbol. MAP1 S and PP2A binding sites are overlapping and found just intracellular to TM4. TM2 and TM3 segments are thought to form the channel pore. Alternative splicing in rodents but not humans produces a twenty amino acid insert (-SRWRRWTCKTEGDSELSLFP-). This area contains potential phosphorylation sequences for PKA, PKC, and CaMKII. Most sites have been proposed by sequence analysis and are not verified. Amino acid numbers appear in orange. Figure based on sequence data from (Andersson et al., 2001).
Figure 3
Figure 3
(A) Schematic representation of NMDAR subunit expression in the developing rat brain. The gray scale gradient shows the differences of each subunit relative to maximum, with the darkest regions reflecting the strongest expression. NR3A appears to be expressed in similar temporal fashion to NR2D, with subunits peaking between P7 and P14. This is contrasted with NR3B, NR2A, and NR2C, which increase developmentally and peak in the third postnatal week. Adapted with permission from (Lujan et al., 2005). (B) Schematic representation of NR3A expression profile and potential roles in the developing human central nervous system. Several key developmental processes in the brain characterize the early postnatal timeframe, when NR3A is maximally expressed: axon and dendrite sprouting, synaptogenesis, myelination, cell death, synapse maturation and elimination (de Graaf-Peters and Hadders-Algra, 2006). The gray scale gradient illustrates the changes in NR3A expression levels, with the darkest regions (child/juvenile stages) reflecting the strongest expression, and low expression seen in the lightest regions (fetal and adult life).
Figure 4
Figure 4
The NR3 subfamily decreases NMDAR-mediated neurotransmission. (A) Model demonstrating the influence of the NR3 subfamily on current flux through NMDARs. NMDARs containing the glutamate-binding NR2 subunits (red) are highly permeable to Ca2+ and dependent upon postsynaptic depolarization due to the Mg2+ block. Conversely, NMDARs containing glycine-binding NR3 subunits (green) flux less current (“i”), are less permeable to Ca2+, and are less sensitive to Mg2+ block. This is demonstrated in panels (B) and (C) by single-channel recordings (used with permission from (Sasaki et al., 2002). These recordings from outside-out patches are taken from oocytes expressing NR1/NR2A/NR3A from injections of cRNA in a (B) 1:1:2 ratio or (C) 1:1:5 ratio and demonstrate the dominant-negative effects of the NR3 subunits on NMDAR-mediated neurotransmission. Dotted red line in (B) indicates high conductance state of a putative NR1/NR2A-receptor, while dotted green line in (C) indicates low conductance state of a putative NR1/NR2A/NR3A-receptor.
Figure 5
Figure 5
NR3A-containing NMDARs may contribute to white matter damage with ischemia. High concentrations of extracellular glutamate caused by reversal of glutamate transport during ischemic conditions can make oligodendrocytes particularly vulnerable to injury. Unlike traditional NMDARs, NR3A-containing receptors may be preferentially activated by glutamate because they are found at high levels in oligodendrocytes and they are insensitive to magnesium block. The resulting calcium influx through NR3A-NMDARs may be sufficient to cause excitotoxic damage to oligodendrocyte processes, ultimately resulting in cell death (indicated by brown color). Modified with permission from (Matute, 2006).
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