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Structural insights into opposing actions of neurosteroids on GABAA receptors
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Journal Article
Structural insights into opposing actions of neurosteroids on GABAA receptors
2023
Overview
γ-Aminobutyric acid type A (GABA
A
) receptors mediate fast inhibitory signaling in the brain and are targets of numerous drugs and endogenous neurosteroids. A subset of neurosteroids are GABA
A
receptor positive allosteric modulators; one of these, allopregnanolone, is the only drug approved specifically for treating postpartum depression. There is a consensus emerging from structural, physiological and photolabeling studies as to where positive modulators bind, but how they potentiate GABA activation remains unclear. Other neurosteroids are negative modulators of GABA
A
receptors, but their binding sites remain debated. Here we present structures of a synaptic GABA
A
receptor bound to allopregnanolone and two inhibitory sulfated neurosteroids. Allopregnanolone binds at the receptor-bilayer interface, in the consensus potentiator site. In contrast, inhibitory neurosteroids bind in the pore. MD simulations and electrophysiology support a mechanism by which allopregnanolone potentiates channel activity and suggest the dominant mechanism for sulfated neurosteroid inhibition is through pore block.
Legesse et al. present structural studies of a human GABAA receptor in complex with positive and negative modulator neurosteroids, uncovering mechanisms of potentiation and inhibition.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
