{"doi":"10.1101/2020.04.27.063404","title":"Site-specific effects of neurosteroids on GABA <sub>A</sub> receptor activation and desensitization","abstract":"ABSTRACT This study examines how site-specific binding to the three identified neurosteroid binding sites in the α 1 β 3 GABA A receptor (GABA A R) contributes to neurosteroid allosteric modulation. We found that the potentiating neurosteroid, allopregnanolone, but not its inhibitory 3β-epimer epi-allopregnanolone, binds to the canonical β 3 (+)–α 1 (-) intersubunit site that mediates receptor activation by neurosteroids. In contrast, both allopregnanolone and epi-allopregnanolone bind to intrasubunit sites in the β 3 subunit, promoting receptor desensitization and the α 1 subunit promoting ligand-specific effects. Two neurosteroid analogues with diazirine moieties replacing the 3-hydroxyl (KK148 and KK150) bind to all three sites, but do not potentiate GABA A R currents. KK148 is a desensitizing agent, whereas KK150 is devoid of allosteric activity. These compounds provide potential chemical scaffolds for site-specific and general 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 GABA A Rs.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":126610,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9577,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":321072,"name":"Wayland W.L. Cheng","orcid":"0000-0002-9529-9820","position":1,"is_corresponding":false},{"id":321073,"name":"John Bracamontes","orcid":"0000-0003-0826-8872","position":2,"is_corresponding":false},{"id":321074,"name":"Zi-Wei Chen","orcid":"0000-0001-8601-2210","position":3,"is_corresponding":false},{"id":321075,"name":"Lei Wang","orcid":"0000-0002-4572-0269","position":4,"is_corresponding":false},{"id":321076,"name":"Allison L. Germann","orcid":"0000-0002-0544-4896","position":5,"is_corresponding":false},{"id":299099,"name":"Spencer R. Pierce","orcid":"0000-0001-8913-6657","position":6,"is_corresponding":false},{"id":322134,"name":"Thomas C. Senneff","orcid":null,"position":7,"is_corresponding":false},{"id":322135,"name":"Kathiresan Krishnan","orcid":null,"position":8,"is_corresponding":false},{"id":321077,"name":"David E. Reichert","orcid":"0000-0003-3432-8998","position":9,"is_corresponding":false},{"id":246033,"name":"Douglas F. Covey","orcid":"0000-0002-9316-8683","position":10,"is_corresponding":false},{"id":321078,"name":"Gustav Akk","orcid":"0000-0001-6677-0655","position":11,"is_corresponding":false},{"id":321079,"name":"Alex S. Evers","orcid":"0000-0002-0342-0575","position":12,"is_corresponding":false},{"id":321071,"name":"Yusuke Sugasawa","orcid":"0000-0003-1607-0460","position":0,"is_corresponding":true}],"reference_count":78,"raw_metadata":null,"created_at":"2026-07-18T23:15:27.226519Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}