Structure and function of GluN1-3A NMDA receptor excitatory glycine receptor channel

Michalski, Kevin, Furukawa, Hiro (April 2024) Structure and function of GluN1-3A NMDA receptor excitatory glycine receptor channel. Science Advances, 10 (15). eadl5952. ISSN 2375-2548

PDF sciadv.adl5952.pdf - Published Version Available under License Creative Commons Attribution. Download (10MB)

Abstract

N-methyl-d-aspartate receptors (NMDARs) and other ionotropic glutamate receptors (iGluRs) mediate most of the excitatory signaling in the mammalian brains in response to the neurotransmitter glutamate. Uniquely, NMDARs composed of GluN1 and GluN3 are activated exclusively by glycine, the neurotransmitter conventionally mediating inhibitory signaling when it binds to pentameric glycine receptors. The GluN1-3 NMDARs are vital for regulating neuronal excitability, circuit function, and specific behaviors, yet our understanding of their functional mechanism at the molecular level has remained limited. Here, we present cryo-electron microscopy structures of GluN1-3A NMDARs bound to an antagonist, CNQX, and an agonist, glycine. The structures show a 1-3-1-3 subunit heterotetrameric arrangement and an unprecedented pattern of GluN3A subunit orientation shift between the glycine-bound and CNQX-bound structures. Site-directed disruption of the unique subunit interface in the glycine-bound structure mitigated desensitization. Our study provides a foundation for understanding the distinct structural dynamics of GluN3 that are linked to the unique function of GluN1-3 NMDARs.

Item Type:	Paper
Subjects:	bioinformatics Investigative techniques and equipment > microscopy > Cryo-electron microscopy bioinformatics > genomics and proteomics Investigative techniques and equipment bioinformatics > genomics and proteomics > small molecules > NMDA receptor organism description > animal organism description > animal > mammal Investigative techniques and equipment > microscopy bioinformatics > genomics and proteomics > small molecules
CSHL Authors:	Michalski, Kevin Furukawa, Hiro
Communities:	CSHL Cancer Center Program > Cellular Communication in Cancer Program CSHL labs > Furukawa lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	12 April 2024
Date Deposited:	16 Apr 2024 14:24
Last Modified:	16 Apr 2024 14:24
PMCID:	PMC11006217
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/41513

Actions (login required)

Administrator's edit/view item