Structural mechanism of glutamate receptor activation and desensitization

Joel R. Meyerson, Janesh Kumar, Sagar Chittori, Prashant Rao, Jason Pierson, Alberto Bartesaghi, Mark L. Mayer, Sriram Subramaniam

Research output: Contribution to journalArticle

Abstract

Ionotropic glutamate receptors are ligand-gated ion channels that mediate excitatory synaptic transmission in the vertebrate brain. To gain a better understanding of how structural changes gate ion flux across the membrane, we trapped rat AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) and kainate receptor subtypes in their major functional states and analysed the resulting structures using cryo-electron microscopy. We show that transition to the active state involves a 'corkscrew' motion of the receptor assembly, driven by closure of the ligandbinding domain. Desensitization is accompanied by disruption of the amino-terminal domain tetramer in AMPA, but not kainate, receptors with a two-fold to four-fold symmetry transition in the ligand-binding domains in both subtypes. The 7.6 A structure of a desensitized kainate receptor shows how these changes accommodate channel closing. These findings integrate previous physiological, biochemical and structural analyses of glutamate receptors and provide a molecular explanation for key steps in receptor gating.

Original languageEnglish (US)
Pages (from-to)328-334
Number of pages7
JournalNature
Volume514
Issue number7522
DOIs
StatePublished - Aug 3 2014
Externally publishedYes

Fingerprint

Kainic Acid Receptors
Glutamate Receptors
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Ligand-Gated Ion Channels
Isoxazoles
Cryoelectron Microscopy
Ionotropic Glutamate Receptors
Synaptic Transmission
Vertebrates
Ions
Ligands
Membranes
Brain

ASJC Scopus subject areas

  • General

Cite this

Meyerson, J. R., Kumar, J., Chittori, S., Rao, P., Pierson, J., Bartesaghi, A., ... Subramaniam, S. (2014). Structural mechanism of glutamate receptor activation and desensitization. Nature, 514(7522), 328-334. https://doi.org/10.1038/nature13603

Structural mechanism of glutamate receptor activation and desensitization. / Meyerson, Joel R.; Kumar, Janesh; Chittori, Sagar; Rao, Prashant; Pierson, Jason; Bartesaghi, Alberto; Mayer, Mark L.; Subramaniam, Sriram.

In: Nature, Vol. 514, No. 7522, 03.08.2014, p. 328-334.

Research output: Contribution to journalArticle

Meyerson, JR, Kumar, J, Chittori, S, Rao, P, Pierson, J, Bartesaghi, A, Mayer, ML & Subramaniam, S 2014, 'Structural mechanism of glutamate receptor activation and desensitization', Nature, vol. 514, no. 7522, pp. 328-334. https://doi.org/10.1038/nature13603
Meyerson JR, Kumar J, Chittori S, Rao P, Pierson J, Bartesaghi A et al. Structural mechanism of glutamate receptor activation and desensitization. Nature. 2014 Aug 3;514(7522):328-334. https://doi.org/10.1038/nature13603
Meyerson, Joel R. ; Kumar, Janesh ; Chittori, Sagar ; Rao, Prashant ; Pierson, Jason ; Bartesaghi, Alberto ; Mayer, Mark L. ; Subramaniam, Sriram. / Structural mechanism of glutamate receptor activation and desensitization. In: Nature. 2014 ; Vol. 514, No. 7522. pp. 328-334.
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