GABA-independent activation of GABAB receptor by mechanical forces

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