Structural insights into opposing actions of neurosteroids on GABAA receptors

Legesse, Dagimhiwat H.; Fan, Chen; Teng, Jinfeng; Zhuang, Yuxuan; Howard, Rebecca J.; Noviello, Colleen M.; Lindahl, Erik; Hibbs, Ryan E.

doi:10.1038/s41467-023-40800-1

Title: Structural insights into opposing actions of neurosteroids on GABA_A receptors

Journal Article · 22 August 2023 · Nature Communications

DOI: https://doi.org/10.1038/s41467-023-40800-1 · OSTI ID:2424192

Legesse, Dagimhiwat H. ^[1];

^[2]; Teng, Jinfeng ^[3];

^[2];

^[2]; Noviello, Colleen M. ^[3];

^[4];

^[5]

UT Southwestern Medical Center, Dallas, TX (United States)
Stockholm University, Solna (Sweden)
University of California San Diego, La Jolla, CA (United States)
Stockholm University, Solna (Sweden); KTH Royal Institute of Technology, Solna (Sweden)
UT Southwestern Medical Center, Dallas, TX (United States); University of California San Diego, La Jolla, CA (United States)

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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Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States). Environmental Molecular Sciences Laboratory (EMSL)

Sponsoring Organization:: CPRIT Core Facility Support Award; National Institutes of Health (NIH); Stockholm University; Swedish Research Council; USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF); USDOE Office of Science (SC), Biological and Environmental Research (BER); Welch Foundation

Grant/Contract Number:: AC05-76RL01830

OSTI ID:: 2424192

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 14; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Title: Structural insights into opposing actions of neurosteroids on GABA_A receptors