Structural Basis of GABA <sub>B</sub> Receptor Activation during Evolution
GABA<sub>B</sub> receptor is a Class C G protein-coupled receptor (GPCR) for γ-aminobutyric acid (GABA), the principal inhibitory neurotransmitter. It forms an obligatory heterodimer consisting of two subunits, GB1 and GB2. Whether the activation mechanism of the GABA<sub>B</sub> receptor is conserved during evolution remains unknown. Here, the cryogenic electron microscopy (cryo-EM) structures of the drosophila GABA<sub>B</sub> receptor in both antagonist-bound inactive state and GABA-bound active state in complex with G<sub>i</sub> protein are reported. The drosophila GABA<sub>B</sub> receptor exhibits an asymmetric activation, mirroring its human homolog. However, a larger inactive interface prevents drosophila GABA<sub>B</sub> receptor constitutive activity. Four key residues, which are not conserved in drosophila GABA<sub>B</sub> receptor, are responsible for the activity of the positive allosteric modulator in its human homolog. Whereas the intracellular loop 2 of drosophila GB2 (dGB2) is less involved, the ordered C terminus of dGB2 and its corresponding region in its human homolog are required for G protein coupling. These evolutionary variations provide a complete understanding of the activation mechanism of the GABA<sub>B</sub> receptor and new insights for future development of allosteric modulators for medication and insecticides.
Authors
- Guofei Hou
- Chanjuan Xu (ORCID: https://orcid.org/0000-0002-5640-1896)
- Jun He (ORCID: https://orcid.org/0000-0003-0270-9729)
- Dandan Shen (ORCID: https://orcid.org/0000-0001-8757-4602)
- Su‐Yu Ji
- Cheng Deng (ORCID: https://orcid.org/0000-0002-5296-8879)
- Philippe Rondard (ORCID: https://orcid.org/0000-0003-1134-2738)
- Haidi Chen (ORCID: https://orcid.org/0000-0002-5105-5306)
- Jianfeng Liu (ORCID: https://orcid.org/0000-0002-0284-8377)
- Liang Li (ORCID: https://orcid.org/0000-0002-6562-7838)
- Yan Zhang (ORCID: https://orcid.org/0000-0003-2189-0244)
- Jiayin Liang (ORCID: https://orcid.org/0000-0002-8934-6213)
- Binqian Zou
- Shenglan Zhang (ORCID: https://orcid.org/0009-0005-3274-7656)
- Cangsong Shen (ORCID: https://orcid.org/0000-0002-5312-1821)
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université de Montpellier (FR)
- Sichuan University (CN)
- Guangzhou Institutes of Biomedicine and Health (CN)
- Sir Run Run Shaw Hospital (CN)
- Guangzhou Regenerative Medicine and Health Guangdong Laboratory (CN)
- Institut de Génomique Fonctionnelle (FR)
- Huazhong University of Science and Technology (CN)
- Zhejiang University (CN)
- University of Hong Kong (HK)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-07-12
- DOI
- https://doi.org/10.1002/advs.202509440
- Primary Topic
- Receptor Mechanisms and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Ministry of Science and Technology
- Institut National de la Santé et de la Recherche Médicale
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- National Key Research and Development Program of China
- Fundamental Research Funds for the Central Universities
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences