Structural mechanism of glutamate receptor activation and desensitization

• Published in: Nature (London) Vol. 514; no. 7522; pp. 328 - 334
• Main Authors: Meyerson, Joel R., Kumar, Janesh, Chittori, Sagar, Rao, Prashant, Pierson, Jason, Bartesaghi, Alberto, Mayer, Mark L., Subramaniam, Sriram
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.10.2014; Nature Publishing Group
• Subjects: 101/28; 147/28; 631/378/2586; 631/535/1258; Amino acids; Analysis; Animals; Binding Sites; Cell receptors; Cryoelectron Microscopy; Crystal structure; GluK2 Kainate Receptor; Glutamic Acid - chemistry; Glutamic Acid - metabolism; Glutamic Acid - pharmacology; Humanities and Social Sciences; Ion Channel Gating - drug effects; Ligands; Models, Molecular; multidisciplinary; Nervous system; Physiological aspects; Protein Structure, Tertiary - drug effects; Rats; Receptors, AMPA - antagonists & inhibitors; Receptors, AMPA - chemistry; Receptors, AMPA - metabolism; Receptors, AMPA - ultrastructure; Receptors, Kainic Acid - chemistry; Receptors, Kainic Acid - metabolism; Receptors, Kainic Acid - ultrastructure; Science; Studies; Symmetry; United States
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature13603

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. Cryo-electron microscopy is used to visualize the AMPA receptor GluA2 and the kainate receptor GluK2 in several functional states — having access to so many different structural states has enabled the authors to propose a molecular model for the gating cycle of glutamate receptors. Three-state solution for glutamate receptor structure Understanding the structural basis of the transition from closed to active and desensitized conformations is central to deciphering the function of ionotropic glutamate receptors — NMDA receptors, AMPA receptors, delta receptors, and kainate receptors — as mediators of excitatory synaptic transmission in the central nervous system. Ligand binding at the receptor's extracellular surface opens the cation-selective pore, and channel opening is followed by desensitization, which closes the pore. In this study, Sriram Subramaniam and colleagues use cryo-electron microscopy to visualize the AMPA receptor GluA2 and the kainate receptor GluK2 in several functional states — resting, open and desensitized. Based on theses structures, the authors propose a molecular model for the gating cycle of glutamate receptors.