Structural Basis of Functional Transitions in Mammalian NMDA Receptors

Chou, Tsung‐Han; Tajima, N.; Hernandez, Annabel Romero; Furukawa, Hiro

doi:10.1016/j.cell.2020.05.052

Cited by 84 publications

(106 citation statements)

References 79 publications

(106 reference statements)

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“…Definitive evidence indicates that agonist-dependent gating of NMDA receptors require functional LBDs and TMD and their cooperation (4,5,7,(57)(58)(59). Further, CTD domains modulate channel conductance and channel open probability, and mediate effects on conductance, calcium-permeability, and gating by intracellular effectors (31,60,61).…”

Section: Discussionmentioning

confidence: 99%

“…This knowledge is important because the large size of NTD and CTD layers of the NMDA receptors, which represent more than half their mass, precludes their structural examination in intact form. In fact, the most comprehensive structural models reported to date for tetrameric NMDA receptors describe CTD-lacking receptors (4)(5)(6)(7)(8)58,59,62). Further, tetrameric receptors that lack both the NTD and the CTD layers, represent more amenable targets for high resolution structural studies (7).…”

Section: Discussionmentioning

confidence: 99%

“…The electrical signals generated by NMDA receptors result from complex reaction mechanisms that include agonist-binding reactions and dynamic isomerizations that accomplish gate opening, channel desensitization, and mode transitions (1)(2)(3). Despite increasing knowledge of NMDA receptor architectures, the specific structures that support activation, desensitization and moding remain under investigation (4)(5)(6)(7)(8)(9).…”

Section: Introducyionmentioning

confidence: 99%

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Contributions by N-terminal Domains to NMDA Receptor Currents

Amico-Ruvio

Paganelli

Abbott

et al. 2020

Preprint

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To investigate the role of the N-terminal do-mains (NTDs) in NMDA receptor signaling we used kinetic analyses of one-channel currents and compared the reaction mechanism of re-combinant wild-type GluN1/GluN2A and GluN1/GluN2B receptors with those observed for NDT-lacking receptors. We found that trun-cated receptors maintained the fundamental gat-ing mechanism characteristic of NMDA recep-tors, which includes a multi-state activation se-quence, desensitization steps, and mode transi-tions. This result establishes that none of the functionally-defined NMDA receptor activation events require the NTD. Notably, receptors that lacked the entire NTD layer retained isoform-specific kinetics. Together with previous reports, these results demonstrate that the entire gating machinery of NMDA receptors resides within a core domain that contains the ligand-binding and the channel-forming transmembrane domains, whereas the NTD and C-terminal layers serve modulatory functions, exclusively

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introducyionmentioning

confidence: 99%

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Contributions by N-terminal Domains to NMDA Receptor Currents

Amico-Ruvio

Paganelli

Abbott

et al. 2020

Preprint

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“…B, each GluN subunit is made up of four structural modules -the N-terminal domain that can bind allosteric modulators, the agonist binding domain for glutamate/glycine recognition, the transmembrane domain that allows the ion channel to span the lipid bilayer of cell membrane, and the C-terminal domain that signals receptor trafficking and synaptic localization (Paoletti et al 2013;Karakas & Furukawa, 2014). Agonist binding to GluN2 increases the tension of the ABD-TMD linkers to relieve ion channel gating, whereas antagonism of GluN1/2 mediates gating through relaxing the GluN2 ABD-TMD linkers (Chou et al 2020). C, NMDAR activity can be modulated pharmacologically through multiple target sites.…”

Section: Figure 1 Nmdar Composition Diversity and Structural Domainsmentioning

confidence: 99%

“…Agonist binding to GluN2 increases the tension of the ABD–TMD linkers to relieve ion channel gating, whereas antagonism of GluN1/2 mediates gating through relaxing the GluN2 ABD–TMD linkers (Chou et al . 2020). C , NMDAR activity can be modulated pharmacologically through multiple target sites.…”

Section: Introductionmentioning

confidence: 99%

NMDA receptors in axons: there's no coincidence

Wong

Rannio

Jones

et al. 2020

The Journal of Physiology

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conducted his PhD research in Prof. Christine Holt's lab at the University of Cambridge, where he revealed how RNA trafficking and highly localized protein synthesis in axons regulate synaptogenesis in vivo. For his HBHL and FRQS Postdoctoral Fellowships, he joined Prof. Jesper Sjöström's lab to pursue his keen interest in presynaptic plasticity in neurotransmission. P. Jesper Sjöström is Associate Professor in Neuroscience at McGill University's Centre for Research in Neuroscience and holds an FRQS Chercheur-Boursier Senior award. His team explores plasticity in the brain using quadruple patch-clamp, two-photon microscopy, optogenetics and computer modelling. His research has unveiled plasticity learning rules, neocortical connectivity patterns and unconventional forms of NMDA receptor signalling. He

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Insights into the regulation of podocyte and glomerular function by lactate and its metabolic sensor G‐protein‐coupled receptor 81

Grochowalska

Pikuł

Piwkowska

2022

Journal Cellular Physiology

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Podocytes and their foot processes are an important cellular layer of the renal filtration barrier that is involved in regulating glomerular permeability. Disturbances of podocyte function play a central role in the development of proteinuria in diabetic nephropathy. The retraction and effacement of podocyte foot processes that form slit diaphragms are a common feature of proteinuria. Correlations between the retraction of foot processes and the development of proteinuria are not well understood. Unraveling peculiarities of podocyte energy metabolism notably under diabetic conditions will provide insights into the pathogenesis of diabetic nephropathy. Intracellular metabolism in the cortical area of podocytes is regulated by glycolysis, whereas energy balance in the central area is controlled by oxidative phosphorylation and glycolysis. High glucose concentrations were recently reported to force podocytes to switch from mitochondrial oxidative phosphorylation to glycolysis, resulting in lactic acidosis. In this review, we hypothesize that the lactate receptor G-protein-coupled receptor 81 (also known as hydroxycarboxylic acid receptor 81) may contribute to the control of podocyte function in both health and disease.

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Structural Basis of Functional Transitions in Mammalian NMDA Receptors

Cited by 84 publications

References 79 publications

Contributions by N-terminal Domains to NMDA Receptor Currents

Contributions by N-terminal Domains to NMDA Receptor Currents

NMDA receptors in axons: there's no coincidence

Insights into the regulation of podocyte and glomerular function by lactate and its metabolic sensor G‐protein‐coupled receptor 81

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