Structural Mechanism of Functional Modulation by Gene Splicing in NMDA Receptors.

Regan MC, Grant T, McDaniel MJ, Karakas E, Zhang J, Traynelis SF, Grigorieff N, Furukawa H
Neuron. 2018 98 (3): 521-529.e3

PMID: 29656875 · PMCID: PMC5963293 · DOI:10.1016/j.neuron.2018.03.034

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.

Copyright © 2018 Elsevier Inc. All rights reserved.

MeSH Terms (11)

Animals Cell Line Female HEK293 Cells Humans Insecta Protein Splicing Protein Structure, Secondary Protein Structure, Tertiary Receptors, N-Methyl-D-Aspartate Xenopus laevis

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