{"id":{"repo_id":"utswmed","oai_identifier":"oai:utswmed-ir.tdl.org:2152.5/10717"},"canonical_url":"https://search.dev.ndltd.org/etd/utswmed/oai:utswmed-ir.tdl.org:2152.5/10717","repository":{"repo_id":"utswmed","name":"University of Texas Southwestern Medical Center","base_url":"https://utswmed-ir.tdl.org/server/oai/request"},"display":{"title":"Understanding the Structure and Function of GABAA Receptors Using Cryo-Electron Microscopy","abstract":"The general metadata -- e.g., title, author, abstract, subject headings, etc. -- is publicly available, but access to the submitted files is restricted to UT Southwestern campus access and/or authorized UT Southwestern users.","abstract_html":"The general metadata -- e.g., title, author, abstract, subject headings, etc. -- is publicly available, but access to the submitted files is restricted to UT Southwestern campus access and/or authorized UT Southwestern users.","abstract_has_math":false,"creators":["Legesse, Dagimhiwat Hailu"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Bai, Xiaochen","Hibbs, Ryan E.","Blount, Paul","Chen, Zhe"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025-09-08T21:53:27Z","date_published":"2025-09-08T21:53:27Z","updated_at":"2026-07-24T05:52:20Z","subjects":["Neurosteroids","Neurotransmitter Agents","Receptors, GABA-A","gamma-Aminobutyric Acid","Brain"],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["1535537001"],"render_values":[{"text":"1535537001","href":null,"code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/2152.5/10717","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Bai, Xiaochen","Hibbs, Ryan E.","Blount, Paul","Chen, Zhe"]},{"key":"dc:creator","label":"Author","values":["Legesse, Dagimhiwat Hailu"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2025-09-08T21:53:27Z","2023-08","August 2023","2025-09-08T21:53:28Z"]},{"key":"dc:type","label":"Dc Type","values":["Thesis","text"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Neurosteroids","Neurotransmitter Agents","Receptors, GABA-A","gamma-Aminobutyric Acid","Brain"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2152.5/10717","1535537001"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["The general metadata -- e.g., title, author, abstract, subject headings, etc. -- is publicly available, but access to the submitted files is restricted to UT Southwestern campus access and/or authorized UT Southwestern users.","Pages 17-156 are misnumbered as pages 15-154.","γ-Aminobutyric acid type A (GABAA) receptors are essential for maintaining the delicate balance of excitatory and inhibitory signaling in the brain, playing a pivotal role in regulating neuronal function and communication. These receptors are targeted by a wide range of therapeutic compounds, including anxiolytics, sedatives, and anticonvulsants, as well as endogenous neurosteroids that modulate their function. Among these neurosteroids, a subset acts as positive allosteric modulators of GABAA receptors, enhancing the inhibitory effects of GABA. Allopregnanolone, a prominent member of this group, is the only drug specifically approved for the treatment of postpartum depression, demonstrating the clinical relevance of these modulators. While recent advances in structural, physiological, and photolabeling studies have provided a growing consensus on the binding sites of positive modulators, the exact mechanism by which they potentiate GABA activation remains a subject of ongoing investigation. In contrast, the binding sites, and modes of action of negative modulators, which are other neurosteroids that inhibit GABAA receptor function, are still under debate and require further elucidation. The first part of this thesis describes the work I have done during the last two years, during which I determined structures of a synaptic GABAA receptor bound to allopregnanolone and two inhibitory sulfated neurosteroids, providing new insights into their respective modes of action. Our findings reveal that allopregnanolone binds at the receptor-bilayer interface, occupying a consensus potentiator site, while the inhibitory neurosteroids interact with the receptor at a distinct location within the pore. By employing molecular dynamics (MD) simulations and electrophysiological experiments, we propose a mechanistic model that accounts for the potentiating effects of allopregnanolone on channel activity. Furthermore, our results suggest that the primary mechanism underlying the inhibitory actions of sulfated neurosteroids is the obstruction of the pore, leading to reduced ion flow and channel activity. These findings contribute to our understanding of GABAA receptor modulation and may have implications for the development of novel therapeutic agents targeting these receptors."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Understanding the Structure and Function of GABAA Receptors Using Cryo-Electron Microscopy"]}]}],"canonical_facts":{"dc:contributor":["Bai, Xiaochen","Hibbs, Ryan E.","Blount, Paul","Chen, Zhe"],"dc:creator":["Legesse, Dagimhiwat Hailu"],"dc:date":["2025-09-08T21:53:27Z","2023-08","August 2023","2025-09-08T21:53:28Z"],"dc:description":["The general metadata -- e.g., title, author, abstract, subject headings, etc. -- is publicly available, but access to the submitted files is restricted to UT Southwestern campus access and/or authorized UT Southwestern users.","Pages 17-156 are misnumbered as pages 15-154.","γ-Aminobutyric acid type A (GABAA) receptors are essential for maintaining the delicate balance of excitatory and inhibitory signaling in the brain, playing a pivotal role in regulating neuronal function and communication. These receptors are targeted by a wide range of therapeutic compounds, including anxiolytics, sedatives, and anticonvulsants, as well as endogenous neurosteroids that modulate their function. Among these neurosteroids, a subset acts as positive allosteric modulators of GABAA receptors, enhancing the inhibitory effects of GABA. Allopregnanolone, a prominent member of this group, is the only drug specifically approved for the treatment of postpartum depression, demonstrating the clinical relevance of these modulators. While recent advances in structural, physiological, and photolabeling studies have provided a growing consensus on the binding sites of positive modulators, the exact mechanism by which they potentiate GABA activation remains a subject of ongoing investigation. In contrast, the binding sites, and modes of action of negative modulators, which are other neurosteroids that inhibit GABAA receptor function, are still under debate and require further elucidation. The first part of this thesis describes the work I have done during the last two years, during which I determined structures of a synaptic GABAA receptor bound to allopregnanolone and two inhibitory sulfated neurosteroids, providing new insights into their respective modes of action. Our findings reveal that allopregnanolone binds at the receptor-bilayer interface, occupying a consensus potentiator site, while the inhibitory neurosteroids interact with the receptor at a distinct location within the pore. By employing molecular dynamics (MD) simulations and electrophysiological experiments, we propose a mechanistic model that accounts for the potentiating effects of allopregnanolone on channel activity. Furthermore, our results suggest that the primary mechanism underlying the inhibitory actions of sulfated neurosteroids is the obstruction of the pore, leading to reduced ion flow and channel activity. These findings contribute to our understanding of GABAA receptor modulation and may have implications for the development of novel therapeutic agents targeting these receptors."],"dc:format":["application/pdf"],"dc:identifier":["https://hdl.handle.net/2152.5/10717","1535537001"],"dc:language":["en"],"dc:subject":["Neurosteroids","Neurotransmitter Agents","Receptors, GABA-A","gamma-Aminobutyric Acid","Brain"],"dc:title":["Understanding the Structure and Function of GABAA Receptors Using Cryo-Electron Microscopy"],"dc:type":["Thesis","text"]},"updated_at":"2026-07-24T05:52:20Z"}