Nature Structural & Molecular Biology
- 13, 1120 - 1127 (2006)
Published online: 19 November 2006; | doi:10.1038/nsmb1178
Conformational restriction blocks glutamate receptor desensitizationMatthew C Weston1, Peter Schuck2, Alokesh Ghosal3, Christian Rosenmund1 & Mark L Mayer31
Departments of Neuroscience and Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA. 2
Protein Biophysics Resource, Division of Bioengineering and Physical Science, Office of Research Services, US National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA. 3
Laboratory of Cellular and Molecular Neurophysiology, Porter Neuroscience Research Center, National Institute of Child Health and Human Development, US National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA.
Correspondence should be addressed to Mark L Mayer mayerm@mail.nih.gov Desensitization is a universal feature of ligand-gated ion channels. Using the crystal structure of the GluR2 L483Y mutant channel as a guide, we attempted to build non-desensitizing kainate-subtype glutamate receptors. Success was achieved for GluR5, GluR6 and GluR7 with intermolecular disulfide cross-links but not by engineering the dimer interface. Crystallographic analysis of the GluR6 Y490C L752C dimer revealed relaxation from the active conformation, which functional studies reveal is not sufficient to trigger desensitization. The equivalent non-desensitizing cross-linked GluR2 mutant retained weak sensitivity to a positive allosteric modulator, which had no effect on GluR2 L483Y. These results establish that the active conformation of AMPA and kainate receptors is conserved and further show that their desensitization requires dimer rearrangements, that subtle structural differences account for their diverse functional properties and that the ligand-binding core dimer is a powerful regulator of ion-channel activity.
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