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A biased ligand for OXE-R uncouples Gα and Gβγ signaling within a heterotrimer
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A biased ligand for OXE-R uncouples Gα and Gβγ signaling within a heterotrimer
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Journal Article
A biased ligand for OXE-R uncouples Gα and Gβγ signaling within a heterotrimer
2012
Overview
The first small-molecule inhibitor of chemoattractant GPCR OXE-R disrupts signaling downstream of Gβγ but not Gα
i/o
, providing evidence that signaling bias can occur between Gβγ and Gα subunits within a heterotrimer.
Differential targeting of heterotrimeric G protein versus β-arrestin signaling are emerging concepts in G protein–coupled receptor (GPCR) research and drug discovery, and biased engagement by GPCR ligands of either β-arrestin or G protein pathways has been disclosed. Herein we report on a new mechanism of ligand bias to titrate the signaling specificity of a cell-surface GPCR. Using a combination of biomolecular and virtual screening, we identified the small-molecule modulator Gue1654, which inhibits Gβγ but not Gα signaling triggered upon activation of Gα
i
-βγ by the chemoattractant receptor OXE-R in both recombinant and human primary cells. Gue1654 does not interfere nonspecifically with signaling directly at or downstream of Gβγ. This hitherto unappreciated mechanism of ligand bias at a GPCR highlights both a new paradigm for functional selectivity and a potentially new strategy to develop pathway-specific therapeutics.
Publisher
Nature Publishing Group US
