Structural basis for GABAA receptor potentiation by neurosteroids
Paul S Miller1, Suzanne Scott1,2, Simonas Masiulis1,2
1Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Nature Structural & Molecular Biology
|October 10, 2017
Summary
Neurosteroids bind to GABAA receptors at a site mechanically linked to the ion channel, modulating receptor function. This structural insight explains how neurosteroids regulate inhibition and offers targets for neurological treatments.
Area of Science:
- Neuroscience
- Structural Biology
- Pharmacology
Background:
- Type A γ-aminobutyric acid receptors (GABAARs) are key inhibitory neurotransmitters in the brain.
- Neurosteroids modulate GABAARs, influencing anxiety, sedation, and anesthesia, but their binding and potentiation mechanisms are unclear.
Purpose of the Study:
- To elucidate the structural basis of neurosteroid binding and potentiation at GABAA receptors.
- To understand how neurosteroids modulate receptor function and channel gating.
Main Methods:
- Reported crystal structures of a chimeric GABAAR construct in apo and pregnanolone-bound states.
- Investigated the mechanical coupling between the neurosteroid-binding site and the ion channel pore.
Main Results:
- Identified a neurosteroid-binding site mechanically coupled to the ion channel pore.
- Demonstrated that this site modulates the desensitization-gate conformation.
- Showed this site mediates physiological potentiation of heteromeric GABAARs and explains epimer-specific modulation.
Conclusions:
- Neurosteroids regulate GABAAR desensitization via a mechanically coupled binding site.
- This mechanism is relevant for understanding neurosteroid action and designing new therapeutics.
- The findings have broad implications for pentameric ligand-gated ion channels.
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