Distinct structure and gating mechanism in diverse NMDA receptors with GluN2C and GluN2D subunits

Zhang, Jilin; Zhang, Ming; Wang, Qinrui; Wen, Han; Wang, Fangjun; Wang, Yuhang; Yao, Fenyong; Song, Nan; Kou, Zeng-Wei; Li, Y; Guo, Fei; Zhu, Shujia

doi:10.1038/s41594-023-00959-z

Cited by 11 publications

(11 citation statements)

References 72 publications

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“…Under apo conditions, we primarily observe a high FRET state of 0.97 which correlates to a FRET distance of approximately 29 Å. This distance agrees with the published cryo-EM structure of the GluN1/GluN2D receptor bound by glycine and competitive antagonist CPP, where the distance between Phe554 on both GluN1 subunits is approximately 31 Å 29 . This finding is consistent with the GluN1 transmembrane segments in the GluN1/GluN2D receptor being tightly packed and likely representing the closed, inactive channel state of the receptor.…”

Section: Resultssupporting

confidence: 90%

“…Amino-terminal domain conformations dictate differences in receptor activation 22, 50 . Decoupling of the amino-terminal domain upon antagonist or inhibitor binding correlates with lower activity of GluN1/GluN2A and GluN1/GluN2B receptors 29, 51 . To test if a similar shift in conformational landscape underlies lower activity of the GluN1/GluN2D receptor, we studied distances across the GluN2 subunit amino-terminal domain in GluN2D- and GluN2A-containing receptors.…”

Section: Resultsmentioning

confidence: 99%

“…While several cryo-EM structures of the agonist-bound GluN1/GluN2A and GluN1/GluN2D receptors have been solved, the conformational differences underlying their differences in function could not be clearly identified 28, 29, 30, 31, 32 . Additionally, there are currently no apo state structures of the full-length GluN1/GluN2A or GluN1/GluN2D receptors.…”

Section: Introductionmentioning

confidence: 99%

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Bi-directional allosteric pathway in NMDA receptor activation and modulation

Bender,

Chakraborty,

Durham

et al. 2024

Preprint

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N-methyl-D-aspartate (NMDA) receptors are ionotropic glutamate receptors involved in learning and memory. NMDA receptors primarily comprise two GluN1 and two GluN2 subunits. The GluN2 subunit dictates biophysical receptor properties, including the extent of receptor activation and desensitization. GluN2A- and GluN2D-containing receptors represent two functional extremes. To uncover the conformational basis of their functional divergence, we utilized single-molecule fluorescence resonance energy transfer to probe the extracellular domains of these receptor subtypes under resting and ligand-bound conditions. We find that the conformational profile of the GluN2 amino-terminal domain correlates with the disparate functions of GluN2A- and GluN2D-containing receptors. Changes at the pre-transmembrane segments inversely correlate with those observed at the amino-terminal domain, confirming direct allosteric communication between these domains. Additionally, binding of a positive allosteric modulator at the transmembrane domain shifts the conformational profile of the amino-terminal domain towards the active state, revealing a bidirectional allosteric pathway between extracellular and transmembrane domains.

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Section: Resultssupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Bi-directional allosteric pathway in NMDA receptor activation and modulation

Bender,

Chakraborty,

Durham

et al. 2024

Preprint

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“…However, in the low P o GluN2D, the fully agonist-bound receptor exhibits a super-compact NTD conformation, also observed recently in structural studies. 38,39 Our results suggest that distinct occupancy of three common classes of conformations (splayed, compact, and super-compact) in apo, partially, and fully liganded conformations in different receptor subtypes gives rise to their distinct properties (Fig. 5A).…”

Section: Discussionmentioning

confidence: 75%

“…24,[30][31][32]22 Structural studies have transformed our understanding of NMDAR conformation by capturing each diheterotetrameric subtype at high resolution. 3,4,[33][34][35][36][37][38][39] Though distinct conformations have been observed in different subtypes and in different ligand conditions, it remains difficult to understand how subtype-specific gating emerges without observing the conformations adopted in each subtype in the resting state and with glycine or glutamate alone.…”

Section: Introductionmentioning

confidence: 99%

Conformational basis of subtype-specific allosteric control of NMDA receptor gating

Bleier,

Ribeiro Furtado de Mendonca,

Habrian

et al. 2024

Preprint

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SummaryN-methyl-D-aspartate receptors are ionotropic glutamate receptors that are integral to synaptic transmission and plasticity. Variable GluN2 subunits in diheterotetrameric receptors with identical GluN1 subunits set very different functional properties, which support their individual physiological roles in the nervous system. To understand the conformational basis of this diversity, we assessed the conformation of the common GluN1 subunit in receptors with different GluN2 subunits using single-molecule fluorescence resonance energy transfer (smFRET). We established smFRET sensors in the ligand binding domain and modulatory amino-terminal domain to study an apo-like state and partially liganded activation intermediates, which have been elusive to structural analysis. Our results demonstrate a strong, subtype- specific influence of apo and glutamate-bound GluN2 subunits on GluN1 rearrangements, suggesting a conformational basis for the highly divergent levels of receptor activity, desensitization and agonist potency. Chimeric analysis reveals structural determinants that contribute to the subtype differences. Our study provides a framework for understanding GluN2-dependent functional properties and could open new avenues for subtype-specific modulation.

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N‐methyl‐d‐aspartate receptors: Structure, function, and role in organophosphorus compound poisoning

Kolić,

Kovarik

2024

BioFactors

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Acute organophosphorus compound (OP) poisoning induces symptoms of the cholinergic crises with the occurrence of severe epileptic seizures. Seizures are induced by hyperstimulation of the cholinergic system, but are enhanced by hyperactivation of the glutamatergic system. Overstimulation of muscarinic cholinergic receptors by the elevated acetylcholine causes glutamatergic hyperexcitation and an increased influx of Ca2+ into neurons through a type of ionotropic glutamate receptors, N‐methyl‐d‐aspartate (NMDA) receptors (NMDAR). These excitotoxic signaling processes generate reactive oxygen species, oxidative stress, and activation of the neuroinflammatory response, which can lead to recurrent epileptic seizures, neuronal cell death, and long‐term neurological damage. In this review, we illustrate the NMDAR structure, complexity of subunit composition, and the various receptor properties that change accordingly. Although NMDARs are in normal physiological conditions important for controlling synaptic plasticity and mediating learning and memory functions, we elaborate the detrimental role NMDARs play in neurotoxicity of OPs and focus on the central role NMDAR inhibition plays in suppressing neurotoxicity and modulating the inflammatory response. The limited efficacy of current medical therapies for OP poisoning concerning the development of pharmacoresistance and mitigating proinflammatory response highlights the importance of NMDAR inhibitors in preventing neurotoxic processes and points to new avenues for exploring therapeutics for OP poisoning.

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Distinct structure and gating mechanism in diverse NMDA receptors with GluN2C and GluN2D subunits

Cited by 11 publications

References 72 publications

Bi-directional allosteric pathway in NMDA receptor activation and modulation

Bi-directional allosteric pathway in NMDA receptor activation and modulation

Conformational basis of subtype-specific allosteric control of NMDA receptor gating

N‐methyl‐d‐aspartate receptors: Structure, function, and role in organophosphorus compound poisoning

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