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bioRxiv · 10.1101/2025.06.09.658551

GABA-independent activation of GABAB receptor by mechanical forces

Hu, Y.·Zhou, Y.·Lin, L.·Yang, F.·He, F.·Zhang, F.·Song, M.·Shen, C.·Liu, Y.·Xu, C.·Xu, S.·Liu, J.
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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 novel type of 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 previously unrecognized function of GABAB receptor in mechano-transduction, uncovering a novel ligand-independent activation mechanism for GPCRs.

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Hu, Y., Zhou, Y., Lin, L., Yang, F., He, F., Zhang, F., Song, M., Shen, C., Liu, Y., Xu, C., Xu, S., Liu, J.. 2025-06-12. GABA-independent activation of GABAB receptor by mechanical forces. https://doi.org/10.1101/2025.06.09.658551

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