GABA-independent activation of GABAB receptor by mechanical forces

Yujia Huo, Yiwei Zhou, Li Lin, Fan Yang, Jiyong Meng, Feiteng He, Fengfan Zhang, Mengdan Song, Cangsong Shen, Yuxuan Liu, Philippe Rondard, Chanjuan Xu (), X. Z. Shawn Xu () and Jianfeng Liu ()
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Yujia Huo: Huazhong University of Science and Technology
Yiwei Zhou: Huazhong University of Science and Technology
Li Lin: Huazhong University of Science and Technology
Fan Yang: Huazhong University of Science and Technology
Jiyong Meng: Huazhong University of Science and Technology
Feiteng He: Huazhong University of Science and Technology
Fengfan Zhang: Huazhong University of Science and Technology
Mengdan Song: Huazhong University of Science and Technology
Cangsong Shen: Huazhong University of Science and Technology
Yuxuan Liu: Huazhong University of Science and Technology
Philippe Rondard: INSERM
Chanjuan Xu: Huazhong University of Science and Technology
X. Z. Shawn Xu: University of Michigan
Jianfeng Liu: Huazhong University of Science and Technology

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract The heterodimeric GABAB receptor, composed of GB1 and GB2 subunits, is a metabotropic G protein-coupled receptor (GPCR) activated by the neurotransmitter GABA. GABA binds to the extracellular domain of GB1 to activate G proteins through GB2. Here we show that GABAB receptors can be activated by mechanical forces, such as traction force and shear stress, in a GABA-independent manner. This GABA-independent mechano-activation of GABAB receptor is mediated by a direct interaction between integrins and the extracellular domain of GB1, indicating that GABAB receptor and integrin form a mechano-transduction complex. Mechanistically, shear stress promotes the binding of integrin to GB1 and induces an allosteric re-arrangement of GABAB receptor transmembrane domains towards an active conformation, culminating in receptor activation. Furthermore, we demonstrate that shear stress-induced GABAB receptor activation plays a crucial role in astrocyte remodeling. These findings reveal a role of GABAB receptor in mechano-transduction, uncovering a ligand-independent activation mechanism for GPCRs.

Date: 2025
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DOI: 10.1038/s41467-025-64811-2

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