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Defining the structural relationship between kainate-receptor deactivation and desensitization.
G Brent Dawe1, Maria Musgaard, Elizabeth D Andrews
11] Integrated Program in Neuroscience, McGill University, Montréal, Québec, Canada. [2] Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada. [3].
Nature Structural & Molecular Biology
|August 20, 2013
Summary
Cations act as gatekeepers for kainate-type ionotropic glutamate receptors (KARs), controlling their activation and desensitization. This cation-binding pocket mechanism is unique to KARs among related ligand-gated ion channels.
Area of Science:
- Neuroscience
- Molecular Biology
- Biophysics
Background:
- Desensitization is a key process limiting ligand-gated ion channel (LGIC) activity.
- The structural underpinnings of desensitization are not fully understood but are linked to ligand properties.
Purpose of the Study:
- To investigate the role of an allosteric cation-binding pocket in the desensitization of rat kainate-type ionotropic glutamate receptors (KARs).
- To elucidate the structural basis distinguishing channel deactivation from desensitization in KARs.
Main Methods:
- Investigated the function of KARs using site-directed mutagenesis targeting the cation-binding pocket.
- Analyzed the impact of altering cation-binding affinity on receptor activation and desensitization kinetics.
Main Results:
- Tethering a positive charge to the cation-binding pocket maintained KAR activation, preventing desensitization.
- Mutations disrupting cation binding abolished channel gating.
- Established that deactivation occurs with ligand unbinding before cation dissociation, while desensitization occurs with ligand bound and no cation occupancy.
Conclusions:
- Cations act as critical gatekeepers for KAR gating, uniquely controlling transitions between activated and desensitized states.
- The identified cation-binding mechanism provides a structural distinction between deactivation and desensitization in KARs.
- This cation-dependent gating role is specific to KARs and not observed in related AMPA-type ionotropic glutamate receptors.
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