biostudies-literatureHuo YNational Natural Science Foundation of China (National Science Foundation of China)9843https://www.ebi.ac.uk/biostudies/studies/S-EPMC12595035biostudies-literatureUnknown16(1)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.Nature communicationsGABA-independent activation of GABA<sub>B</sub> receptor by mechanical forces.PMC1259503532271198324210033233004982320108021He FZhang FLiu JShawn Xu XZXu CShen CZhou YYang FLiu YSong MHuo YMeng JRondard PLin LfalseGABA-independent activation of GABA<sub>B</sub> receptor by mechanical forces.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.2025-01-01T00:00:00Z2025 Nov2026-06-05T14:49:00.051Z2026-05-18T03:08:19.803ZS-EPMC125950354120359510.1038/s41467-025-64811-2