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Author Notes:

Hiro Furukawa: furukawa@cshl.edu

M.C.R., M.J.M., E.K., J.Z., H.F. and S.T. conceived and performed experiments involving electrophysiology.

T.G., E.K., H.F., and N.G. solved the cryo-EM structure.

M.C.R. and H.F. wrote the manuscript.

We thank Zhiheng Yu, Chuan Hong, Rick Huang, and M. Jason de la Cruz at the Janelia EM facility; and Noriko Simorowski for excellent technical support.

We also thank Pierre Paoletti for critical reading of this manuscript.

Authors declare no conflict of interests.


Research Funding:

This work was supported by NIH grants NS036654 (SFT); NS093753 (MCR); MH085926 and GM105730 (HF); Stanley Institute of Cognitive Genomics (HF);and Burroughs Wellcome Fund (HF).


  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Neurosciences & Neurology
  • COOT

Structural Mechanism of Functional Modulation by Gene Splicing in NMDA Receptors


Journal Title:



Volume 98, Number 3


, Pages 521-+

Type of Work:

Article | Post-print: After Peer Review


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. Alternative gene splicing has a profound effect on NMDA receptor function. Through cryo-EM and electrophysiology, Regan et al. discovered that the position of an alternatively spliced motif alters receptor function by stabilizing intersubunit and interdomain interfaces within the protein.

Copyright information:

© 2018 Elsevier Inc.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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