Publication Date:
2014-08-15
Description:
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 (alpha-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 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199900/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199900/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Meyerson, Joel R -- Kumar, Janesh -- Chittori, Sagar -- Rao, Prashant -- Pierson, Jason -- Bartesaghi, Alberto -- Mayer, Mark L -- Subramaniam, Sriram -- Z01 BC010278-10/Intramural NIH HHS/ -- ZIA BC010826-07/Intramural NIH HHS/ -- England -- Nature. 2014 Oct 16;514(7522):328-34. doi: 10.1038/nature13603. Epub 2014 Aug 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Cell Biology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland 20892, USA. ; Laboratory of Cellular and Molecular Neurophysiology, Porter Neuroscience Research Center, NICHD, NIH, Bethesda, Maryland 20892, USA. ; FEI Company, Hillsboro, Oregon 97124, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25119039" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Binding Sites
;
*Cryoelectron Microscopy
;
Glutamic Acid/chemistry/metabolism/pharmacology
;
Ion Channel Gating/drug effects
;
Ligands
;
Models, Molecular
;
Protein Structure, Tertiary/drug effects
;
Rats
;
Receptors, AMPA/antagonists & inhibitors/chemistry/*metabolism/*ultrastructure
;
Receptors, Kainic Acid/chemistry/*metabolism/*ultrastructure
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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