Molecular Mechanisms of NMDA Receptor Function and Regulation

Tajima, Nami (February 2018) Molecular Mechanisms of NMDA Receptor Function and Regulation. Biophysical Journal, 114 (3, Sup). 25a. ISSN 0006-3495

URL: https://www.sciencedirect.com/science/article/pii/...
DOI: 10.1016/j.bpj.2017.11.182

Abstract

N-methyl-D-aspartate receptors (NMDARs) belong to a class of ionotropic glutamate receptors that are crucially involved in brain development and function, and NMDAR dysfunction is implicated in various neurological diseases. The transmembrane ion channel opens upon membrane depolarization and agonist binding to the extracellular ligand-binding domain, while the extracellular amino terminal domain (ATD) tightly regulates functional properties. Although NMDAR structures representing inhibited states are available, there is no clear understanding of how conformational alteration in the extracellular domains regulate NMDAR activity. We will describe the first structural evidence for conformational alteration of the NMDARs and how the NMDARs are activated and inhibited. To understand the regulation mechanisms above, we conducted structural and functional studies. First we present the first structural evidence for conformational alteration in the NMDAR ATD wherein the bilobed structure of the ATD opens and closes. On the basis of structure-based mutagenesis coupled to electrophysiology, we show that stabilization of open and closed cleft conformations leads to activation and allosteric inhibition, respectively. In order to understand the conformational change in the context of full length, we obtained the intact NMDAR structure in an active conformation by cryo-electron microscopy in the absence of inhibitors. These studies allow us to uncover the conformational change in multiple domains and molecular mechanisms.

Item Type: Paper
Additional Information: Meeting abstract
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > NMDA receptor
CSHL Authors:
Communities: CSHL labs > Furukawa lab
Depositing User: Matt Covey
Date: 2 February 2018
Date Deposited: 21 May 2018 19:18
Last Modified: 21 May 2018 19:18
URI: http://repository.cshl.edu/id/eprint/36581

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