Structural Mechanism of Functional Modulation by Gene Splicing in NMDA Receptors

Regan, M. C., Grant, T., McDaniel, M. J., Karakas, E., Zhang, J., Traynelis, S. F., Grigorieff, N., Furukawa, H. (May 2018) Structural Mechanism of Functional Modulation by Gene Splicing in NMDA Receptors. Neuron, 98 (3). pp. 521-529. ISSN 0896-6273

URL: https://www.ncbi.nlm.nih.gov/pubmed/29656875
DOI: 10.1016/j.neuron.2018.03.034

Abstract

Alternative gene splicing gives rise to N-methyl-D-aspartate (NMDA) receptor ion channels with defined functional properties and unique contributions to calcium signaling in a given chemical environment in the mammalian brain. Splice variants possessing the exon-5-encoded motif at the amino-terminal domain (ATD) of the GluN1 subunit are known to display robustly altered deactivation rates and pH sensitivity, but the underlying mechanism for this functional modification is largely unknown. Here, we show through cryoelectron microscopy (cryo-EM) that the presence of the exon 5 motif in GluN1 alters the local architecture of heterotetrameric GluN1-GluN2 NMDA receptors and creates contacts with the ligand-binding domains (LBDs) of the GluN1 and GluN2 subunits, which are absent in NMDA receptors lacking the exon 5 motif. The unique interactions established by the exon 5 motif are essential to the stability of the ATD/LBD and LBD/LBD interfaces that are critically involved in controlling proton sensitivity and deactivation.

Item Type: Paper
Uncontrolled Keywords: NMDA receptor alternative splicing cryo-EM electrophysiology
Subjects: Investigative techniques and equipment > microscopy > Cryo-electron microscopy
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 May 2018
Date Deposited: 25 Apr 2018 18:48
Last Modified: 14 Jun 2018 19:31
PMCID: PMC5963293
Related URLs:
URI: http://repository.cshl.edu/id/eprint/36509

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