GABA-independent activation of GABAB receptor by mechanical forces
Yujia Huo1, Yiwei Zhou1, Li Lin1
1Cellular Signaling Laboratory, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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.
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