Structural Insights into Opposing Actions of Neurosteroids on GABA A Receptors
Nature communications(2023)
摘要
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.
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关键词
Computational biology and bioinformatics,Cryoelectron microscopy,Ion channels,Ion channels in the nervous system,Permeation and transport,Science,Humanities and Social Sciences,multidisciplinary
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