Defining the structural relationship between kainate-receptor deactivation and desensitization
| Autor: | G. Brent Dawe, Bryan A. Daniels, Elizabeth D. Andrews, Derek Bowie, Maria Musgaard, Mark R. P. Aurousseau, Philip C. Biggin |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Models
Molecular Cation binding Stereochemistry medicine.medical_treatment Allosteric regulation Kainate receptor Gating Molecular Dynamics Simulation Ligands Article 03 medical and health sciences 0302 clinical medicine Receptors Kainic Acid Structural Biology medicine Animals Humans Receptors AMPA Molecular Biology Ion channel 030304 developmental biology Desensitization (medicine) 0303 health sciences Binding Sites Chemistry Recombinant Proteins Rats Protein Subunits HEK293 Cells Mutagenesis Site-Directed Biophysics Ligand-gated ion channel Protein Multimerization Ion Channel Gating 030217 neurology & neurosurgery Ionotropic effect |
| Zdroj: | Nature structural & molecular biology |
| ISSN: | 1545-9985 1545-9993 |
| Popis: | Desensitization is an important mechanism that curtails 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 the physicochemical properties of the bound ligand. 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, identifying cations as gatekeepers of KAR gating, a role unique among even closely-related LGICs. |
| Databáze: | OpenAIRE |
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