GABA-independent activation of GABA<sub>B</sub> receptor by mechanical forces.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 41203595.
- Also identified by DOI 10.1038/s41467-025-64811-2 and PMC identifier 12595035.
- Licence recorded as CC BY-NC-ND.
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Abstract
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.
Medical subject headings
- Receptors, GABA-B
- gamma-Aminobutyric Acid
- Mechanotransduction, Cellular