Site-specific effects of neurosteroids on GABAA receptor activation and desensitization

Author:

Sugasawa Yusuke1ORCID,Cheng Wayland WL1ORCID,Bracamontes John R1,Chen Zi-Wei12ORCID,Wang Lei1,Germann Allison L1,Pierce Spencer R1,Senneff Thomas C1,Krishnan Kathiresan3,Reichert David E24,Covey Douglas F1235,Akk Gustav12,Evers Alex S123ORCID

Affiliation:

1. Department of Anesthesiology, Washington University in St. Louis, St. Louis, United States

2. Taylor Family Institute for Innovative Psychiatric Research, Washington University in St. Louis, St. Louis, United States

3. Department of Developmental Biology, Washington University in St. Louis, St. Louis, United States

4. Department of Radiology, Washington University in St. Louis, St. Louis, United States

5. Department of Psychiatry, Washington University in St. Louis, St. Louis, United States

Abstract

This study examines how site-specific binding to three identified neurosteroid-binding sites in the α1β3 GABAA receptor (GABAAR) contributes to neurosteroid allosteric modulation. We found that the potentiating neurosteroid, allopregnanolone, but not its inhibitory 3β-epimer epi-allopregnanolone, binds to the canonical β3(+)–α1(-) intersubunit site that mediates receptor activation by neurosteroids. In contrast, both allopregnanolone and epi-allopregnanolone bind to intrasubunit sites in the β3 subunit, promoting receptor desensitization and the α1 subunit promoting effects that vary between neurosteroids. Two neurosteroid analogues with diazirine moieties replacing the 3-hydroxyl (KK148 and KK150) bind to all three sites, but do not potentiate GABAAR currents. KK148 is a desensitizing agent, whereas KK150 is devoid of allosteric activity. These compounds provide potential chemical scaffolds for neurosteroid antagonists. Collectively, these data show that differential occupancy and efficacy at three discrete neurosteroid-binding sites determine whether a neurosteroid has potentiating, inhibitory, or competitive antagonist activity on GABAARs.

Funder

National Institutes of Health

Taylor Family Institute for Innovative Psychiatric Research

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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