Interdomain interactions in AMPA and kainate receptors regulate affinity for glutamate.
Ionotropic glutamate receptors perform diverse functions in the nervous system. As a result, multiple receptor subtypes have evolved with different kinetics, ion permeability, expression patterns, and regulation by second messengers. Kainate receptors show slower recovery from desensitization and have different affinities for agonists than AMPA receptors. Based on analysis of ligand binding domain crystal structures, we identified interdomain interactions in the agonist-bound state that are conserved in kainate receptors and absent in AMPA receptors. Mutations in GluR6 designed to disrupt these contacts reduced agonist apparent affinity, speeded up receptor deactivation and increased the rate of recovery from desensitization. Conversely, introduction of mutations in GluR2 that enabled additional interdomain interactions in the agonist-bound state increased agonist apparent affinity 15-fold, and slowed both deactivation and recovery from desensitization. We conclude that interdomain interactions have evolved as a distinct mechanism that contributes to the unique kinetic properties of AMPA and kainate receptors.
Weston
Matthew C
MC
Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA.
Gertler
Christoph
C
Mayer
Mark L
ML
Rosenmund
Christian
C
D000818:Animals; D001667:Binding, Competitive / Q000502:physiology; D002460:Cell Line; D003461:Crystallography / Q000379:methods; D004594:Electrophysiology; D018698:Glutamic Acid / Q000378:metabolism*; D018257:Helix-Loop-Helix Motifs / Q000502:physiology; D006801:Humans; D008024:Ligands; D017354:Point Mutation / Q000502:physiology; D015202:Protein Engineering; D017434:Protein Structure, Tertiary / Q000502:physiology; D051381:Rats; D018091:Receptors, AMPA / Q000819:agonists / Q000235:genetics* / Q000378:metabolism*; D018092:Kainic Acid Receptors / Q000819:agonists / Q000235:genetics* / Q000378:metabolism*; D000097806:GluK2 Kainate Receptor
D018698:Glutamic Acid; D008024:Ligands; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D000097806:GluK2 Kainate Receptor; C104722:glutamate receptor ionotropic, AMPA 2