GluN3A NMDA receptor subunits: more enigmatic than ever?

Crawley, Oliver; Conde-Dusman, María J; Pérez‐Otaño, Isabel

doi:10.1113/jp280879

Cited by 23 publications

(22 citation statements)

References 103 publications

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“…To date, only few GluN3 modulators have been reported ( Crawley et al, 2022 ). Due to the low sequence identity and structural conservation between GluN3 and the other NMDAR subunits, GluN3 subunits are hyposensitive to both competitive modulators acting on GluN2 subunits and broad-spectrum channel blockers ( Chatterton et al, 2002 ; McClymont et al, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

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Identification of a Subtype-Selective Allosteric Inhibitor of GluN1/GluN3 NMDA Receptors

et al. 2022

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N-methyl-D-aspartate receptors (NMDARs) are Ca2+-permeable ionotropic glutamate receptors (iGluRs) in the central nervous system and play important roles in neuronal development and synaptic plasticity. Conventional NMDARs, which typically comprise GluN1 and GluN2 subunits, have different biophysical properties than GluN3-containing NMDARs: GluN3-containing NMDARs have smaller unitary conductance, less Ca2+-permeability and lower Mg2+-sensitivity than those of conventional NMDARs. However, there are very few specific modulators for GluN3-containing NMDARs. Here, we developed a cell-based high-throughput calcium assay and identified 3-fluoro-1,2-phenylene bis (3-hydroxybenzoate) (WZB117) as a relatively selective inhibitor of GluN1/GluN3 receptors. The IC50 value of WZB117 on GluN1/GluN3A receptors expressed in HEK-293 cells was 1.15 ± 0.34 μM. Consistently, WZB117 exhibited strong inhibitory activity against glycine-induced currents in the presence of CGP-78608 but only slightly affected the NMDA-, KA- and AMPA-induced currents in the acutely isolated rat hippocampal neurons. Among the four types of endogenous currents, only the first one is primarily mediated by GluN1/GluN3 receptors. Mechanistic studies showed that WZB117 inhibited the GluN1/GluN3A receptors in a glycine-, voltage- and pH-independent manner, suggesting it is an allosteric modulator. Site-directed mutagenesis and chimera construction further revealed that WZB117 may act on the GluN3A pre-M1 region with key determinants different from those of previously identified modulators. Together, our study developed an efficient method to discover modulators of GluN3-containing NMDARs and characterized WZB117 as a novel allosteric inhibitor of GluN1/GluN3 receptors.

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Section: Discussionmentioning

confidence: 99%

“…Much less is known about GluN3-containing NMDARs (hereafter GluN3-NMDARs) than about conventional NMDARs ( Crawley et al, 2022 ). Coassembly with GluN3 (3A-3B) subunits dramatically changes the biophysical properties of NMDARs by promoting smaller unitary conductance, less Ca 2+ -permeability and lower Mg 2+ -sensitivity.…”

Section: Introductionmentioning

confidence: 99%

Identification of a Subtype-Selective Allosteric Inhibitor of GluN1/GluN3 NMDA Receptors

et al. 2022

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“…These properties are determined to a large extent by subunit composition and stoichiometry of NMDARs 14 . In adulthood, conventional NMDARs are heterotetramers composed of obligatory GluN1 subunits and regulatory GluN2 subunits, while unconventional GluN1/3 heterotetramers are transiently expressed during early postnatal development 10,15 . The GluN2 subunits contain the ligand-binding site indispensable for the glutamate-gated operation of NMDARs at excitatory synapses 16 .…”

Section: Introductionmentioning

confidence: 99%

Common synaptic phenotypes arising from diverse mutations in the human NMDA receptor subunit GluN2A

Elmasri

Hunter

Winchester

et al. 2020

Preprint

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Dominant mutations in the human gene GRIN2A, encoding NMDA receptor (NMDAR) subunit GluN2A, make a significant and growing contribution to the catalogue of published single-gene epilepsies. Understanding the disease mechanism in these epilepsy patients is complicated by the surprising diversity of effects that the mutations have on NMDARs. We have examined the cell-autonomous impact of 5 severe GluN2A mutations by measuring NMDAR-mediated synaptic currents (NMDAR-EPSCs) in CA1 pyramidal neurons following rescue with human GluN2A mutants. Surprisingly, prolonged NMDAR-EPSC current decay and smaller peak amplitudes were common features of both gain- and loss-of-function mutants despite there being drastic differences between their effects on receptor function and enrichment at synapses. Modelling of NMDARs with mutant properties in CA1 neurons indicates that mutant NMDARs may contribute to broadening of depolarizations during bursts of high-frequency synaptic activity. Overall, the implication is that similar therapeutic approaches may be more widely applicable to patients with GRIN2A-related disorders irrespective of their molecular defect.

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“…Reviews from this event appear in this issue of The Journal of Physiology. The five review articles (Crawley et al 2022;Frydenvang et al 2022;Geoffroy et al 2022;Pampaloni & Plested, 2022;von Engelhardt, 2022) and one Techniques for Physiology paper (Obergrussberger et al 2022) in this issue are a lasting legacy of the day's presentations and provide us with an excellent overview of aspects of contemporary ionotropic glutamate receptor research.…”

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confidence: 99%

“…However, given the modulatory effects of the incorporation of a GluN3 subunit into assemblies of GluN1 and GluN2 NMDA receptor subunits, it seems appropriate to consider all GluN3-containing receptors as welcome members of the family. In their review, Crawley and colleagues assess the temporal and spatial expression pattern of GluN3A subunits, the location of their expression at the synapse and the physiological roles they have in normal brain development (Crawley et al 2022). Like each of the GluN2 NMDA receptor subunits, GluN3A subunits display a unique fingerprint in their expression pattern, and their potential critical role in the early developing brain is underpinned by the fact that their peak expression occurs in the first two postnatal weeks and would appear to be regulated by activity.…”

mentioning

confidence: 99%