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., PNAS - 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.

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.

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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/

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