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Structural insights...
Structural insights into opposing actions of neurosteroids on GABAA receptors
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- Legesse, Dagimhiwat H. (author)
- UT Southwestern Med Ctr, Dept Neurosci, Dallas, TX 75390 USA.
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- Fan, Chen, 1987- (author)
- Stockholms universitet,Institutionen för biokemi och biofysik,Science for Life Laboratory (SciLifeLab),Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Solna, Sweden.
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- Teng, Jinfeng (author)
- Univ Calif San Diego, Dept Neurobiol, La Jolla, CA 92093 USA.
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- Zhuang, Yuxuan (author)
- Stockholms universitet,Institutionen för biokemi och biofysik,Science for Life Laboratory (SciLifeLab),Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Solna, Sweden.
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- Howard, Rebecca J., 1980- (author)
- Stockholms universitet,Institutionen för biokemi och biofysik,Science for Life Laboratory (SciLifeLab),Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Solna, Sweden.
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- Noviello, Colleen M. (author)
- Univ Calif San Diego, Dept Neurobiol, La Jolla, CA 92093 USA.
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- Lindahl, Erik, 1972- (author)
- Stockholms universitet,KTH,Science for Life Laboratory, SciLifeLab,Biofysik,Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Solna, Sweden.,Institutionen för biokemi och biofysik,Science for Life Laboratory (SciLifeLab)
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- Hibbs, Ryan E. (author)
- UT Southwestern Med Ctr, Dept Neurosci, Dallas, TX 75390 USA.;Univ Calif San Diego, Dept Neurobiol, La Jolla, CA 92093 USA.
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UT Southwestern Med Ctr, Dept Neurosci, Dallas, TX 75390 USA Institutionen för biokemi och biofysik (creator_code:org_t)
- Springer Nature, 2023
- 2023
- English.
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
- Related links:
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https://doi.org/10.1...
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Legesse, Dagimhi ...
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Fan, Chen, 1987-
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Teng, Jinfeng
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Zhuang, Yuxuan
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Howard, Rebecca ...
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Noviello, Collee ...
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show more...
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Lindahl, Erik, 1 ...
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Hibbs, Ryan E.
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medicinal Chemis ...
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Biochemistry and ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Neurosciences
- Articles in the publication
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Nature Communica ...
- By the university
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Royal Institute of Technology
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Stockholm University