title: Defining the structural relationship between kainate-receptor deactivation and desensitization.
abstract: Desensitization is an important mechanism curtailing the activity of ligand-gated ion channels (LGICs). Although the structural basis of desensitization is not fully resolved, it is thought to be governed by physicochemical properties of bound ligands. Here, we show the importance of an allosteric cation-binding pocket in controlling transitions between activated and desensitized states of rat kainate-type (KAR) ionotropic glutamate receptors (iGluRs). Tethering a positive charge to this pocket sustains KAR activation, preventing desensitization, whereas mutations that disrupt cation binding eliminate channel gating. These different outcomes explain the structural distinction between deactivation and desensitization. Deactivation occurs when the ligand unbinds before the cation, whereas desensitization proceeds if a ligand is bound without cation pocket occupancy. This sequence of events is absent from AMPA-type iGluRs; thus, cations are identified as gatekeepers of KAR gating, a role unique among even closely related LGICs.
authors: 1] Integrated Program in Neuroscience, McGill University, Montréal, Québec, Canada. [2] Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada. [3].
authors: G Brent
authors: GB
authors: Dawe
authors: Maria
authors: M
authors: Musgaard
authors: Elizabeth D
authors: ED
authors: Andrews
authors: Bryan A
authors: BA
authors: Daniels
authors: Mark R P
authors: MR
authors: Aurousseau
authors: Philip C
authors: PC
authors: Biggin
authors: Derek
authors: D
authors: Bowie
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D016297:Mutagenesis, Site-Directed; D055503:Protein Multimerization; D021122:Protein Subunits; D051381:Rats; D018091:Receptors, AMPA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000097806:GluK2 Kainate Receptor
chemical_list: D008024:Ligands; D021122:Protein Subunits; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D011994:Recombinant Proteins; D000097806:GluK2 Kainate Receptor
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