Mechanisms for zinc and proton inhibition of the GluN1/GluN2A NMDA receptor

Jalali-Yazdi, Farzad; Chowdhury, Sandipan; Yoshioka, Craig; Gouaux, Eric

doi:10.1101/378422

Cited by 32 publications

(55 citation statements)

References 63 publications

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“…9a, b). Moreover, although there may be rearrangements of the extracellular domain at low pH that may disrupt NMDAR channel function 51 , there were no effects of pH on PLA puncta density in WT or I272H GluN1-transfected cells, suggesting that pH does not affect the ability of EphB2 and the NMDAR to interact (Fig. 9a, b.…”

Section: Impact Of Glycosylation Of Glun1 N350 In Hek293t Cellsmentioning

confidence: 96%

“…Substituting histidine at GluN1 hinge region residues should generate a pH-sensitive molecular switch for the EphB-NMDAR interaction [48][49][50] . Because low pH (<6.0) would also alter the pK a of any exposed histidine residues in the extracellular domain, and is known to result in rearrangements of the NMDAR ectodomain 51 , we generated three histidine point mutants in the GluN1 hinge region: I272H, N273H, and R337H. We expect that the WT and I272H mutant GluN1 should interact at both pH 5 and pH 7.3, controlling for the effects of rearrangements.…”

Section: Impact Of Glycosylation Of Glun1 N350 In Hek293t Cellsmentioning

confidence: 99%

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Positive surface charge of GluN1 N-terminus mediates the direct interaction with EphB2 and NMDAR mobility

et al. 2020

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Localization of the N-methyl-D-aspartate type glutamate receptor (NMDAR) to dendritic spines is essential for excitatory synaptic transmission and plasticity. Rather than remaining trapped at synaptic sites, NMDA receptors undergo constant cycling into and out of the postsynaptic density. Receptor movement is constrained by protein-protein interactions with both the intracellular and extracellular domains of the NMDAR. The role of extracellular interactions on the mobility of the NMDAR is poorly understood. Here we demonstrate that the positive surface charge of the hinge region of the N-terminal domain in the GluN1 subunit of the NMDAR is required to maintain NMDARs at dendritic spine synapses and mediates the direct extracellular interaction with a negatively charged phospho-tyrosine on the receptor tyrosine kinase EphB2. Loss of the EphB-NMDAR interaction by either mutating GluN1 or knocking down endogenous EphB2 increases NMDAR mobility. These findings begin to define a mechanism for extracellular interactions mediated by charged domains.

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Section: Impact Of Glycosylation Of Glun1 N350 In Hek293t Cellsmentioning

confidence: 96%

Section: Impact Of Glycosylation Of Glun1 N350 In Hek293t Cellsmentioning

confidence: 99%

Positive surface charge of GluN1 N-terminus mediates the direct interaction with EphB2 and NMDAR mobility

et al. 2020

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“…They are composed of four pore-forming subunits, but may contain several auxiliary subunits and form larger complexes [21,3]. While a recent series of high resolution structures of AMPARs and NMDARs provided important information about their function, these structures were obtained from reconstituted receptors that were altered in different ways to improve their expression and stability [22,23,24,25,26,27,28]. Therefore, there is a need to obtain structures of AMPAR and NMDAR in their native physiological conformations, subunit composition and lipid environment.…”

Section: Introductionmentioning

confidence: 99%

Trans-synaptic assemblies link synaptic vesicles and neuroreceptors

Martínez-Sánchez

Laugks

Kochovski

et al. 2020

Preprint

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Synaptic transmission is characterized by fast, tightly coupled processes and complex signaling pathways that require a distinctly non-random spatial organization of their components. Nanoscale organization of synaptic proteins at glutamatergic synapses was suggested to regulate synaptic plasticity, the process underlying learning and memory. Specifically, direct colocalization of pre- and postsynaptic proteins implicated that the alignment of neurotransmitter release sites with neurotransmitter receptors enables maximal synaptic response. However, direct visualization and the mechanistic understanding of this alignment is lacking. Here we used cryo-electron tomography to visualize synaptic complexes in their native environment with the full complement of their interacting partners, synaptic vesicles and plasma membranes on 2-4 nanometer scale. The application of our recent template-free detection and classification procedure showed that tripartite trans-synaptic assemblies (subcolumns) link synaptic vesicles to postsynaptic receptors, and established that a particular displacement between directly interacting complexes characterizes subcolumns. Furthermore, we obtained de novo average structures of ionotropic glutamate receptors in their physiological composition, embedded in lipid membranes. The data presented support the hypothesis that synaptic function is carried by precisely organized trans-synaptic units. It complements superresolution findings and provides a framework for further exploration of synaptic and other large molecular assemblies that link different cells or cellular regions and may require weak or transient interactions to exert their function.

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“…The GluN2A subunit has a predominant expression at mature synapses and replaces the early‐dominant GluN2B subunit during early postnatal development . Similar to other NMDA subunits, the architecture of GluN2A consists of: (a) an extracellular amino‐terminal domain (ATD) that is involved in allosteric regulation; (b) a ligand binding domain (LBD) that harbors binding sites for glutamate and glycine with highly conserved sequences among GluN2 subunits; (c) a transmembrane domain (TMD) that forms a pore for ion permeability; (d) and an intracellular C‐terminal domain (CTD) that relates to intracellular trafficking and signaling cascades (Figure ) . Inside the ATD of the GluN2A subunit, a binding site with nanomolar affinity towards zinc was identified, which contributes to high sensitivity towards zinc inhibition in comparison with the GluN2B subunit .…”

Section: Introductionmentioning

confidence: 99%

“…(A) Crystal structure of the hetero‐dimeric GluN1/GluN2A receptor complexed with glycine and glutamate (without intracellular domain, PDB ID: 6MML); (B) GluN1/GluN2A ligand binding domain (LBD) complexed with GNE6901 (PDB ID: 5KCJ) (created with PyMOL Molecular Graphics System, Version 2.0 Schrödinger, LLC)…”

Section: Introductionmentioning

confidence: 99%

Recent progress in allosteric modulators for GluN2A subunit and development of GluN2A‐selective nuclear imaging probes

Ametamey

et al. 2019

Labelled Comp Radiopharmac

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N-methyl-D-aspartate (NMDA) receptors play key roles in physiology by regulating the synaptic plasticity and the cellular mechanism involved in learning and memory. The GluN2A subunit is the most abundant expression of NMDA receptors in mature brain, and its dysfunction has been implicated in various neurological disorders. However, the function of GluN2A subunit in physiological and pathological conditions is not yet completely unveil due to the lack of subunit-selective ligands, including specific positron emission tomography (PET)/single photon emission computed tomography (SPECT) imaging probes.In this review, recent progresses in understanding its pathophysiological role, the structure-activity relationship, and the postulated mechanisms of novel GluN2A ligands as well as status of molecular imaging probes for PET are summarized.

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Mechanisms for zinc and proton inhibition of the GluN1/GluN2A NMDA receptor

Abstract: ensemble of conformations under a range of physiologically relevant zinc and proton concentrations. We show how zinc binding to the amino terminal domain elicits structural changes that are transduced though the ligand-binding domain and result in constriction of the ion channel gate.

Cited by 32 publications

References 63 publications

Positive surface charge of GluN1 N-terminus mediates the direct interaction with EphB2 and NMDAR mobility

Positive surface charge of GluN1 N-terminus mediates the direct interaction with EphB2 and NMDAR mobility

Trans-synaptic assemblies link synaptic vesicles and neuroreceptors

Recent progress in allosteric modulators for GluN2A subunit and development of GluN2A‐selective nuclear imaging probes

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