title: Structural mechanism of glutamate receptor activation and desensitization.
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.
authors.affiliation: Laboratory of Cell Biology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Joel R
authors.initials: JR
authors.lastname: Meyerson
authors.affiliation: Laboratory of Cellular and Molecular Neurophysiology, Porter Neuroscience Research Center, NICHD, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Janesh
authors.initials: J
authors.lastname: Kumar
authors.affiliation: Laboratory of Cellular and Molecular Neurophysiology, Porter Neuroscience Research Center, NICHD, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Sagar
authors.initials: S
authors.lastname: Chittori
authors.affiliation: Laboratory of Cell Biology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Prashant
authors.initials: P
authors.lastname: Rao
authors.affiliation: FEI Company, Hillsboro, Oregon 97124, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Pierson
authors.affiliation: Laboratory of Cell Biology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bartesaghi
authors.affiliation: Laboratory of Cellular and Molecular Neurophysiology, Porter Neuroscience Research Center, NICHD, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Mayer
authors.affiliation: Laboratory of Cell Biology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Sriram
authors.initials: S
authors.lastname: Subramaniam
mesh_terms: D000818:Animals; D001665:Binding Sites; D020285:Cryoelectron Microscopy; D018698:Glutamic Acid / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects; D008024:Ligands; D008958:Models, Molecular; D017434:Protein Structure, Tertiary / Q000187:drug effects; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure*; D018092:Kainic Acid Receptors / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure*; D000097806:GluK2 Kainate Receptor
chemical_list: D018698:Glutamic Acid; D008024:Ligands; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D000097806:GluK2 Kainate Receptor; C104722:glutamate receptor ionotropic, AMPA 2