A structurally derived model of subunit‐dependent NMDA receptor function

Gibb, Alasdair J.; Ogden, Kevin K.; McDaniel, Miranda J.; Vance, Katie M.; Kell, Steven A.; Butch, Chris; Burger, Pieter B.; Liotta, Dennis; Traynelis, Stephen F.

doi:10.1113/jp276093

Cited by 46 publications

(67 citation statements)

References 169 publications

(282 reference statements)

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“…Our single channel recordings were performed in 0.5 mM Ca 2+ , which can have a profound effect on single channel properties. The open probability we report here for the WT GluN2A receptor (0.34) is consistent with those determined in the presence of Ca 2+ in cell-attached patches (Dravid et al, 2007;Iacobucci and Popescu, 2017) and in outside-out patches (Gibb et al, 2018;Rycroft and Gibb, 2002;Bhattacharya et al, 2018). Moreover, Iacobucci and Popescu (2017) show the open probability drops by threefold from 0.62 (0 mM Ca 2+ ) to 0.21 (0.5 mM Ca 2+ ), suggesting that the lack of divalent ions in previously published cell-attached patch studies contributes to the higher open probability observed in the absence of extracellular Ca 2+ .…”

Section: Discussionsupporting

confidence: 89%

“…GluN2A-F553A shifted glutamate potency ∼11-fold (EC 50 from 3.6 µM to 0.34 µM) and glycine potency ∼18fold (EC 50 from 1.4 µM to 0.077 µM). Fitted EC 50 values for all mutants can be found in Table 2. open probabilities reported here for WT GluN1/GluN2A receptors are consistent with those reported previously for the same receptors studied in the presence of extracellular calcium at pH 8.0 (Dravid et al, 2007;Chopra et al, 2015;Gibb et al, 2018).…”

Section: Pre-m1 Mutations Alter Nmdar Single Channel Propertiessupporting

confidence: 92%

“…the same functional consequences when expressed in GluN1 (Ogden et al, 2017;Gibb et al, 2018). Because the aromatic network that potentially dictates channel gating is less extensive in GluN1 pre-M1 helix, mutations in this region might have reduced functional consequences.…”

Section: Subunit-specific Pre-m1 Helix Interactionsmentioning

confidence: 99%

“…Although the mechanism of NMDAR gating remains poorly understood, it has been hypothesized that the linker tethering the ABD to the TMD is responsible for facilitating communication between these two domains (Schorge et al, 2005;Sobolevsky et al, 2009;Talukder et al, 2010;Talukder and Wollmuth, 2011;Karakas and Furukawa, 2014;Lee et al, 2014;Gibb et al, 2018;Amin et al, 2020). Thus far, the flexible and dynamic nature of the ABD-TMD linker has prevented high resolution structure of this region, and the structure of the fully open NMDAR pore remains elusive (Tajima et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…By contrast, the pre-M1 helices of these subunits harbor multiple de novo mutations in patients with epilepsy, intellectual disabilities, or developmental delays (Swanger et al, 2016;Ogden et al, 2017;XiangWei et al, 2018;Amin et al, 2020). Within the GluN2A and GluN2B subunits, functional analysis of these disease-associated mutations revealed changes to NMDAR kinetics, further implicating the pre-M1 helix in the gating mechanism (Ogden et al, 2017;Gibb et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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NMDA receptor channel gating control by the pre-M1 helix

McDaniel

Ogden

Kell

et al. 2020

Journal of General Physiology

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The NMDA receptor (NMDAR) is an ionotropic glutamate receptor formed from the tetrameric assembly of GluN1 and GluN2 subunits. Within the flexible linker between the agonist binding domain (ABD) and the M1 helix of the pore-forming transmembrane helical bundle lies a two-turn, extracellular pre-M1 helix positioned parallel to the plasma membrane and in van der Waals contact with the M3 helix thought to constitute the channel gate. The pre-M1 helix is tethered to the bilobed ABD, where agonist-induced conformational changes initiate activation. Additionally, it is a locus for de novo mutations associated with neurological disorders, is near other disease-associated de novo sites within the transmembrane domain, and is a structural determinant of subunit-selective modulators. To investigate the role of the pre-M1 helix in channel gating, we performed scanning mutagenesis across the GluN2A pre-M1 helix and recorded whole-cell macroscopic and single channel currents from HEK293 cell-attached patches. We identified two residues at which mutations perturb channel open probability, the mean open time, and the glutamate deactivation time course. We identified a subunit-specific network of aromatic amino acids located in and around the GluN2A pre-M1 helix to be important for gating. Based on these results, we are able to hypothesize about the role of the pre-M1 helix in other NMDAR subunits based on sequence and structure homology. Our results emphasize the role of the pre-M1 helix in channel gating, implicate the surrounding amino acid environment in this mechanism, and suggest unique subunit-specific contributions of pre-M1 helices to GluN1 and GluN2 gating.

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Section: Discussionsupporting

confidence: 89%

Section: Pre-m1 Mutations Alter Nmdar Single Channel Propertiessupporting

confidence: 92%

Section: Subunit-specific Pre-m1 Helix Interactionsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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NMDA receptor channel gating control by the pre-M1 helix

McDaniel

Ogden

Kell

et al. 2020

Journal of General Physiology

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NMDA Receptors

Gibb¹

2019

Encyclopedia of Life Sciences

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N‐methyl‐D‐aspartate (NMDA) receptors are one type of glutamate receptor. They play key roles in synaptic transmission and plasticity in the central nervous system. They are uniquely activated by simultaneous binding of the amino acids glycine and l ‐glutamate. These receptors are proteins that form an ion channel across the cell membrane, commonly formed by assembly of two glutamate‐binding GluN2 subunits and two glycine‐binding GluN1 subunits. The ion channel opens following receptor activation, allowing Na + and Ca 2+ ions to cross the cell membrane, thus translating the transient chemical signal provided by release of glutamate from a presynaptic neuron, into postsynaptic electrical and biochemical Ca 2+ signals. Crucially, the characteristics of NMDA receptor signalling depend on the receptor subunit composition, particularly the nature of the GluN2 subunits which can be of four different types, creating unique and important variations in properties that provide a rich diversity of NMDA receptor signalling in the brain. Key Concepts NMDA receptor functional diversity is determined by the receptor subunit composition. Key functional attributes of NMDA receptors are the Ca 2+ permeability and Mg 2+ block of the transmembrane ion channel and the slow kinetics of receptor activation which can last for hundreds of milliseconds. The receptor subunits are somewhat modular in nature with key functional attributes depending on particular domains of the subunit protein. Domain interactions are an emerging concept in understanding NMDA receptor structure–function relationships. Allosteric modulators of NMDA receptors can both enhance or inhibit receptor function and provide the future possibility of novel therapeutic approaches to diseases of the nervous system associated with altered NMDA receptor function.

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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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A structurally derived model of subunit‐dependent NMDA receptor function

Cited by 46 publications

References 169 publications

NMDA receptor channel gating control by the pre-M1 helix

NMDA receptor channel gating control by the pre-M1 helix

NMDA Receptors

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

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