Structural mechanism of glutamate receptor activation and desensitization

Joel R. Meyerson, Janesh Kumar, Sagar Chittori, Prashant Rao, Jason Pierson, Alberto Bartesaghi, Mark L. Mayer () and Sriram Subramaniam ()
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Joel R. Meyerson: Laboratory of Cell Biology, Center for Cancer Research, NCI, NIH
Janesh Kumar: Laboratory of Cellular and Molecular Neurophysiology, Porter Neuroscience Research Center, NICHD, NIH
Sagar Chittori: Laboratory of Cellular and Molecular Neurophysiology, Porter Neuroscience Research Center, NICHD, NIH
Prashant Rao: Laboratory of Cell Biology, Center for Cancer Research, NCI, NIH
Jason Pierson: FEI Company
Alberto Bartesaghi: Laboratory of Cell Biology, Center for Cancer Research, NCI, NIH
Mark L. Mayer: Laboratory of Cellular and Molecular Neurophysiology, Porter Neuroscience Research Center, NICHD, NIH
Sriram Subramaniam: Laboratory of Cell Biology, Center for Cancer Research, NCI, NIH

Nature, 2014, vol. 514, issue 7522, 328-334

Abstract: 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 (α-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 ligand-binding 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 Å 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.

Date: 2014
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DOI: 10.1038/nature13603

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