Apr 3, 2020

Multimodal activation of GPR68 (OGR1) probed with a genetically-encoded fluorescent reporter

BioRxiv : the Preprint Server for Biology
A. D. OzkanJerome Jacques Lacroix


G-protein coupled receptor (GPCR) 68 (GPR68, or OGR1) couples extracellular acidifications and mechanical cues to G protein signaling and plays important roles in vascular physiology, neuroplasticity and cancer progression. The mechanism of mechanosensitivity in GPR68 is currently unkonwn. Here, to study this mechanism, we designed a genetically-encoded fluorescent reporter of GPR68 by fusing a cyclic permuted green fluorescent protein to the third intracellular loop of the receptor. Stimulation with fluid shear stress, extracellular acidifications or the synthetic activator ogerin transiently and robustly increases iGlow's baseline fluorescence up to 4-fold. Flow-induced iGlow activation was not suppressed by pharmacological uncoupling of downstream G-protein recruitment, disruption of actin filaments, inhibition of membrane stretch with the peptide toxin GsMTx4, or deletion of a C-terminal amphipathic Helix (Helix 8) proposed to mediate GPCR mechanosensitivity. These results hint that GPR68 uses a hitherto unknown, non-canonical mechanism to sense mechanical forces.

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