Structural insights into opposing actions of neurosteroids on GABAA receptors
Abstract γ-Aminobutyric acid type A (GABAA) receptors mediate fast inhibitory signaling in the brain and are targets of numerous drugs and endogenous neurosteroids. A subset of neurosteroids are GABAA receptor positive allosteric modulators; one of these, allopregnanolone, is the only drug approved...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-40800-1 |
| _version_ | 1827710055834714112 |
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| author | Dagimhiwat H. Legesse Chen Fan Jinfeng Teng Yuxuan Zhuang Rebecca J. Howard Colleen M. Noviello Erik Lindahl Ryan E. Hibbs |
| author_facet | Dagimhiwat H. Legesse Chen Fan Jinfeng Teng Yuxuan Zhuang Rebecca J. Howard Colleen M. Noviello Erik Lindahl Ryan E. Hibbs |
| author_sort | Dagimhiwat H. Legesse |
| collection | DOAJ |
| description | Abstract γ-Aminobutyric acid type A (GABAA) receptors mediate fast inhibitory signaling in the brain and are targets of numerous drugs and endogenous neurosteroids. A subset of neurosteroids are GABAA 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 GABAA receptors, but their binding sites remain debated. Here we present structures of a synaptic GABAA 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. |
| first_indexed | 2024-03-10T17:31:48Z |
| format | Article |
| id | doaj.art-9c3fd95d1605447bb8e398d6acc64164 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:31:48Z |
| publishDate | 2023-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-9c3fd95d1605447bb8e398d6acc641642023-11-20T09:59:43ZengNature PortfolioNature Communications2041-17232023-08-0114111310.1038/s41467-023-40800-1Structural insights into opposing actions of neurosteroids on GABAA receptorsDagimhiwat H. Legesse0Chen Fan1Jinfeng Teng2Yuxuan Zhuang3Rebecca J. Howard4Colleen M. Noviello5Erik Lindahl6Ryan E. Hibbs7Department of Neuroscience, UT Southwestern Medical CenterDept. of Biochemistry and Biophysics, Science for Life Laboratory, Stockholm UniversityDepartment of Neurobiology, University of California San DiegoDept. of Biochemistry and Biophysics, Science for Life Laboratory, Stockholm UniversityDept. of Biochemistry and Biophysics, Science for Life Laboratory, Stockholm UniversityDepartment of Neurobiology, University of California San DiegoDept. of Biochemistry and Biophysics, Science for Life Laboratory, Stockholm UniversityDepartment of Neuroscience, UT Southwestern Medical CenterAbstract γ-Aminobutyric acid type A (GABAA) receptors mediate fast inhibitory signaling in the brain and are targets of numerous drugs and endogenous neurosteroids. A subset of neurosteroids are GABAA 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 GABAA receptors, but their binding sites remain debated. Here we present structures of a synaptic GABAA 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.https://doi.org/10.1038/s41467-023-40800-1 |
| spellingShingle | Dagimhiwat H. Legesse Chen Fan Jinfeng Teng Yuxuan Zhuang Rebecca J. Howard Colleen M. Noviello Erik Lindahl Ryan E. Hibbs Structural insights into opposing actions of neurosteroids on GABAA receptors Nature Communications |
| title | Structural insights into opposing actions of neurosteroids on GABAA receptors |
| title_full | Structural insights into opposing actions of neurosteroids on GABAA receptors |
| title_fullStr | Structural insights into opposing actions of neurosteroids on GABAA receptors |
| title_full_unstemmed | Structural insights into opposing actions of neurosteroids on GABAA receptors |
| title_short | Structural insights into opposing actions of neurosteroids on GABAA receptors |
| title_sort | structural insights into opposing actions of neurosteroids on gabaa receptors |
| url | https://doi.org/10.1038/s41467-023-40800-1 |
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