288: Cryo-EM of rat cerebellar α1/α6 GABAA receptors reveals PZ‑II‑029 binding and β-α-β-α-γ assemblies

Sun C et al., Proc. Natl. Acad. Sci. U.S.A. 2026.123:e2524504123 - Using cryo-EM and mass spectrometry in rat cerebellum, α1- and α6-containing GABAA receptor assemblies (β‑α‑β‑α‑γ stoichiometry) and PZ-II-029 binding were defined. Key terms: GABAA receptor, cerebellum, α6 subunit, cryo-EM, pyrazoloquinolinone. Study Highlights:The study used rat cerebellum tissue and combined confocal immunofluorescence, affinity purification with mass spectrometry, and high-resolution cryo-EM to characterize native α1-containing GABAA receptors. Cryo-EM classification resolved eight distinct α1-containing receptor assemblies that conform to a conserved β-α-β-α-γ arrangement and include previously unreported α6-containing heteromers. Structural models of α6-containing receptors show near-symmetric ECD architecture with conserved GABA-binding geometry and distinct electrostatic differences that may affect ligand kinetics. Binding of the α6-selective pyrazoloquinolinone PZ-II-029 at α+/γ− pockets was visualized and found to induce coordinated outward expansion of the extracellular domain, providing a structural basis for subtype-selective modulation. Conclusion:Native α1-containing cerebellar GABAA receptors adopt a conserved β-α-β-α-γ pentameric scaffold that includes α6 subunits and binds PZ-II-029 at α+/γ− sites, producing extracellular domain expansion. Music:Enjoy the music based on this article at the end of the episode. Article title:Molecular assemblies and pharmacology of cerebellar GABAA receptors First author:Sun C Journal:Proc. Natl. Acad. Sci. U.S.A. 2026.123:e2524504123 DOI:10.1073/pnas.2524504123 Reference:Sun C, Jahncke JN, Wright KM, Gouaux E. Molecular assemblies and pharmacology of cerebellar GABAA receptors. Proc. Natl. Acad. Sci. U.S.A. 2026;123:e2524504123. Published February 6, 2026. https://doi.org/10.1073/pnas.2524504123 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/cerebellar-gabaa-alpha6-assemblies QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-02-12. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited sections cover GABAAR architecture, cerebellar α1/α6 coassembly, native purification and mass spectrometry, cryo-EM assembly identification, PZ-II-029 binding and allosteric effects, ligand-pocket differences, and study limitations.- transcript topics: GABAAR architecture and subunit diversity; Cerebellar distribution of α1 and α6 subunits and mixed α1/α6 assemblies; Native cerebellar receptor purification, nanodisc reconstitution, and mass spectrometry findings; Cryo-EM identification of eight cerebellar GABAAR assemblies and β2-α1-β1-α6-γ2 configuration; PZ-II-029 binding at α+/γ− pockets (α1/γ2 and α6/γ2) and structural consequences; Ligand-induced extracellular-domain expansion and intersubunit distance changes QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 7- claims flagged for review: 0- metadata checks passed: 4- metadata issues found: 0 Metadata Audited:- article_doi- article_title- article_journal- license Factual Items Audited:- Native cerebellar GABAARs include mixed α1 an...