Journal Article

GABA-independent activation of GABA B receptor by mechanical forces

He, Feiteng, Song, Mengdan, Rondard, Philippe, Huo, Yujia, Lin, Li, Liu, Jianfeng, Meng, Jiyong, Zhang, Fengfan, Shen, Cangsong, Zhou, Yiwei, Xu, X Z Shawn, Yang, Fan, Xu, Chanjuan, Liu, Yuxuan

2025

Overview

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

• Subject: Animals / Astrocytes - cytology / Astrocytes - metabolism / gamma-Aminobutyric Acid - metabolism / HEK293 Cells / Humans / Mechanotransduction, Cellular / Mice / Protein Binding / Receptors, GABA-B - chemistry / Receptors, GABA-B - genetics / Receptors, GABA-B - metabolism / Stress, Mechanical