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Updated: Apr 18, 2026
Rapid and Robust Analysis of Cellular and Molecular Polarization Induced by Chemokine Signaling
Published on: December 12, 2014
Biased signaling at chemokine receptors
Jenny Corbisier1, Céline Galès2, Alexandre Huszagh1
1From the Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire and.
Abstract:
The ability of G protein-coupled receptors (GPCRs) to activate selective signaling pathways according to the conformation stabilized by bound ligands (signaling bias) is a challenging concept in the GPCR field. Signaling bias has been documented for several GPCRs, including chemokine receptors. However, most of these studies examined the global signaling bias between G protein- and arrestin-dependent pathways, leaving unaddressed the potential bias between particular G protein subtypes. Here, we investigated the coupling selectivity of chemokine receptors CCR2, CCR5, and CCR7 in response to various ligands with G protein subtypes by using bioluminescence resonance energy transfer biosensors monitoring directly the activation of G proteins. We also compared data obtained with the G protein biosensors with those obtained with other functional readouts, such as β-arrestin-2 recruitment, cAMP accumulation, and calcium mobilization assays. We showed that the binding of chemokines to CCR2, CCR5, and CCR7 activated the three Gαi subtypes (Gαi1, Gαi2, and Gαi3) and the two Gαo isoforms (Gαoa and Gαob) with potencies that generally correlate to their binding affinities. In addition, we showed that the binding of chemokines to CCR5 and CCR2 also activated Gα12, but not Gα13. For each receptor, we showed that the relative potency of various agonist chemokines was not identical in all assays, supporting the notion that signaling bias exists at chemokine receptors.
Insights
Chemokine receptors CCR2, CCR5, and CCR7 exhibit signaling bias, activating specific G protein subtypes (Gαi, Gαo, Gα12) differently based on ligand binding, revealing pathway selectivity beyond traditional G protein vs. arrestin bias.
Area of Science:
- Biochemistry
- Molecular Pharmacology
- Cell Signaling
Background:
- G protein-coupled receptors (GPCRs) can stabilize distinct conformations upon ligand binding, leading to biased signaling pathways.
- While G protein- vs. arrestin-dependent pathway bias is known for GPCRs, bias among specific G protein subtypes remains less understood.
- Chemokine receptors (e.g., CCR2, CCR5, CCR7) are crucial in immune responses and are implicated in signaling bias.
Purpose of the Study:
- To investigate the coupling selectivity of chemokine receptors CCR2, CCR5, and CCR7 towards different G protein subtypes.
- To determine if signaling bias exists among specific G protein subtypes activated by chemokine receptor ligands.
- To compare G protein activation data with other functional assays like β-arrestin recruitment and second messenger signaling.
Main Methods:
- Utilized bioluminescence resonance energy transfer (BRET) biosensors to directly monitor G protein activation by chemokine receptors.
- Tested the activation of Gαi (Gαi1, Gαi2, Gαi3), Gαo (Gαoa, Gαob), Gα12, and Gα13 subtypes.
- Compared BRET data with results from β-arrestin-2 recruitment, cAMP accumulation, and calcium mobilization assays.
Main Results:
- Chemokines binding to CCR2, CCR5, and CCR7 activated Gαi and Gαo subtypes with potencies generally correlating to binding affinities.
- CCR5 and CCR2 also activated Gα12, but not Gα13, upon chemokine binding.
- Agonist chemokines displayed differential potencies across various assays for each receptor, confirming signaling bias among G protein subtypes.
Conclusions:
- Chemokine receptors exhibit signaling bias not only between G protein and arrestin pathways but also among specific G protein subtypes.
- Ligand-induced conformational changes dictate the selective activation of distinct G protein subtypes by chemokine receptors.
- Understanding this nuanced signaling bias is critical for developing targeted therapeutics for chemokine receptor-mediated diseases.
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