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Hydroxycarboxylic acid receptor 3 and GPR84 signaling with potential implications for immune cell function
Wednesday, 09/15/2021 @ 3:00 PM - EST
- Dr. Claudia Stäubert -
- Leipzig University -
- Leipzig, Germany -
Abstract
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 HCA3, which regulate metabolism and immune functions. Although both receptors are coupled to Gi proteins, share at least one agonist, and show overlapping tissue expression, GPR84 exerts pro-inflammatory effects whereas HCA3 is involved in anti-inflammatory responses.
We analyzed signaling kinetics of both HCA3 and GPR84, to unravel signal transduction components that may explain their physiological differences. We found that HCA3 signaling and trafficking depend on the dynamin-2 function. Activation of HCA3 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. Analyses of freshly isolated neutrophils showed that HCA3 signaling counteracts their GPR84-mediated activation.
In summary, our results highlight that biased agonism is a physiological property of HCA3 and GPR84 with relevance for innate immune functions potentially to differentiate between endogenous, non-pathogenic compounds and compounds originating from e.g. pathogenic bacteria.
About Claudia Stäubert
Claudia received her degree in biochemistry from Leipzig University (Germany) being already fascinated by the versatility, signal transduction, and pharmacology of G protein-coupled receptors (GPCRs). This fascination, accompanying and repeatedly challenging her ever since, had started during Claudia’s stay as a scholarship student in the lab of Prof. Thue Schwartz (Copenhagen, Denmark). During her Ph.D. focused on evolutionary aspects of GPCRs, integrated into the International Max Planck Research School “The Leipzig School of Human Origins”, Claudia received a scholarship from the “Studienstiftung des Deutschen Volkes".
As a postdoc in the lab of Dr. Anders Nordström (Umeå, Sweden), Claudia broadened her methodical and scientific expertise to cellular metabolism and drug resistance phenomenon applying Liquid Chromatography-Mass spectrometry-based metabolomics analyses. Since 2014, Claudia is leading a research group at the Rudolf Schönheimer Institute of Biochemistry in Leipzig (Germany) focused on signal transduction, intracellular trafficking, and evolution of metabolite-sensing GPCRs with the ultimate goal to understand their role for immune cell function and cancer cell metabolism.
Author list and affiliations
Anna Peters 1, Philipp Rabe 1, Aenne-Dorothea Liebing 1, Petra Krumbholz 1, Anders Nordström 2, Robert Kraft 3, Elisabeth Jäger 4, Claudia Stäubert 1
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1 Rudolf Schönheimer Institute of Biochemistry, Faculty of Medicine, Leipzig University, Johannisallee 30, 04103 Leipzig, Germany
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2 Swedish Metabolomics Centre, Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, Linnaeus väg 6, 901 87 Umeå, Sweden
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3 Carl Ludwig Institute for Physiology, Faculty of Medicine, Leipzig University, Liebigstraße 27, 04103 Leipzig, Germany
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4 Cedars-Sinai Medical Center, Department of Pathology, 8700 Beverly Blvd, 90048 Los Angeles (CA), USA
Claudia Stäubert on the web
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