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<p>The heterodimeric GABA<sub>B</sub> 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 GABA<sub>B</sub> 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 GABA<sub>B</sub> receptor is mediated by a direct interaction between integrins and the extracellular domain of GB1, indicating that GABA<sub>B</sub> 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 GABA<sub>B</sub> receptor transmembrane domains towards an active conformation, culminating in receptor activation. Furthermore, we demonstrate that shear stress-induced GABA<sub>B</sub> receptor activation plays a crucial role in astrocyte remodeling. These findings reveal a role of GABA<sub>B</sub> receptor in mechano-transduction, uncovering a ligand-independent activation mechanism for GPCRs.</p>

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GABA-independent activation of GABAB receptor by mechanical forces

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月7日

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  • 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,
  • Jianfeng Liu

摘要

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.