Key result
Activation of HCA3 by 3-hydroxyoctanoic acid but not 3-hydroxydecanoic acid leads to β-arrestin-2 recruitment, demonstrating natural biased signaling of structurally similar agonists.
Why the study?
Although both GPR84 and HCA 3 couple to G i proteins, share an agonist, and have overlapping tissue expression, GPR84 is pro-inflammatory while HCA 3 is anti-inflammatory, prompting investigation into their signaling kinetics.
Structurally similar endogenous and bacteria-derived metabolites induce distinct, biased signaling pathways via HCA3 and GPR84, which may explain their opposing roles in immune regulation.
Answers are grounded in this paper and cite their sources.
May inform metabolite-specific immune modulation via HCA3; leaves open translation of biased signaling to human disease or therapy.
Background Medium-chain fatty acids and their 3-hydroxy derivatives are metabolites endogenously produced in humans, food-derived or originating from bacteria. They activate G protein-coupled receptors, including GPR84 and HCA 3 , which regulate metabolism and immune functions. Although both receptors are coupled to G i proteins, share at least one agonist and show overlapping tissue expression, GPR84 exerts pro-inflammatory effects whereas HCA 3 is involved in anti-inflammatory responses. Here, we analyzed signaling kinetics of both HCA 3 and GPR84, to unravel signal transduction components that may explain their physiological differences. Methods To study the signaling kinetics and components involved in signal transduction of both receptors we applied the label-free dynamic mass redistribution technology in combination with classical cAMP, ERK signaling and β-arrestin-2 recruitment assays. For phenotypical analyses, we used spheroid cell culture models. Results We present strong evidence for a natural biased signaling of structurally highly similar agonists at HCA 3 and GPR84. We show that HCA 3 signaling and trafficking depends on dynamin-2 function. Activation of HCA 3 by 3-hydroxyoctanoic acid but not 3-hydroxydecanoic acid leads to β-arrestin-2 recruitment, which is relevant for cell-cell adhesion. GPR84 stimulation with 3-hydroxydecanoic acid causes a sustained ERK activation but activation of GPR84 is not followed by β-arrestin-2 recruitment. Conclusions In summary, our results highlight that biased agonism is a physiological property of HCA 3 and GPR84 with relevance for innate immune functions potentially to differentiate between endogenous, non-pathogenic compounds and compounds originating from e.g. pathogenic bacteria.
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Peters et al. (2020) studied In vitro cell signaling (HCA3 and GPR84). 3-hydroxyoctanoic acid (3HO) and 3-hydroxydecanoic acid (3HDec) was evaluated on Receptor signaling kinetics and β-arrestin-2 recruitment. Activation of HCA3 by 3-hydroxyoctanoic acid but not 3-hydroxydecanoic acid leads to β-arrestin-2 recruitment, demonstrating natural biased signaling of structurally similar agonists.
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