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| Title | Molecular assemblies and pharmacology of cerebellar GABA receptors. |
|---|---|
| Journal, issue, pages | Proc Natl Acad Sci U S A, Vol. 123, Issue 6, Page e2524504123, Year 2026 |
| Publish date | Feb 10, 2026 |
 Authors | Chang Sun / Jennifer N Jahncke / Kevin M Wright / Eric Gouaux /  |
| PubMed Abstract | GABA receptors (GABARs) mediate fast inhibitory neurotransmission in the brain and are assembled from 19 subunit isoforms into multiple pentameric assemblies. Although α1-containing GABARs are ...GABA receptors (GABARs) mediate fast inhibitory neurotransmission in the brain and are assembled from 19 subunit isoforms into multiple pentameric assemblies. Although α1-containing GABARs are broadly expressed and are pharmacologically important, the molecular diversity of native α1-based assemblies in specific brain regions remains incompletely understood. Here, we use immunofluorescence, mass spectrometry, and cryogenic electron microscopy (cryo-EM) to characterize the spatial distribution, subunit composition, and structural architecture of native α1-containing GABARs in the rat cerebellum. Confocal microscopy reveals robust colocalization of α1 and γ2 subunits across cerebellar layers, including prominent labeling at glomerular synapses. Biochemical purification and proteomic analysis identify a range of α, β, and γ subunits, along with abundant α6 and δ subunits. Using cryo-EM and automated subunit identification, we resolve eight α1-containing receptor assemblies, including the first structure of α6-containing receptors. We further determine the binding mode of the α6-selective pyrazoloquinolinone modulator PZ-II-029 at the α/γ interface, showing ligand-induced expansion of the entire extracellular domain (ECD). Together, our study defines the structure and subunit composition of the α1-containing cerebellar GABARs and elaborates the molecular interactions between native receptors and pyrazoloquinolinone, thereby laying the groundwork for brain region and subunit-specific pharmacology. |
 External links | Proc Natl Acad Sci U S A / PubMed:41650215 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 2.74 - 2.93 Å |
| Structure data | EMDB-70872, PDB-9oum: EMDB-70873, PDB-9oun: EMDB-70874, PDB-9ouo: EMDB-70875, PDB-9oup: EMDB-70876, PDB-9ouq: EMDB-70877, PDB-9our: EMDB-70889, PDB-9ov4: |
| Chemicals |  ChemComp-ABU:  ChemComp-NAG:  PDB-1cep: |
| Source |
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 Keywords | MEMBRANE PROTEIN / neurotransmitter receptor / cys-loop receptor / ligand-gated ion channel |
rattus norvegicus (Norway rat)
mus musculus (house mouse)