Embelin and its derivatives unravel the signaling, proinflammatory and antiatherogenic properties of GPR84 receptor

Pharmacological Research : the Official Journal of the Italian Pharmacological Society
Ibragim GaidarovDavid J Unett

Abstract

GPR84 is an orphan G-protein coupled receptor, expressed on monocytes, macrophages and neutrophils and is significantly upregulated by inflammatory stimuli. The physiological role of GPR84 remains largely unknown. Medium chain fatty acids (MCFA) activate the receptor and have been proposed to be its endogenous ligands, although the high concentrations of MCFAs required for receptor activation generally exceed normal physiological levels. We identified the natural product embelin as a highly potent and selective surrogate GPR84 agonist (originally disclosed in patent application WO2007027661A2, 2007) and synthesized close structural analogs with widely varying receptor activities. These tools were used to perform a comprehensive study of GPR84 signaling and function in recombinant cells and in primary human macrophages and neutrophils. Activation of recombinant GPR84 by embelin in HEK293 cells results in Gi/o as well as G12/13-Rho signaling. In human macrophages, GPR84 initiates PTX sensitive Erk1/2 and Akt phosphorylation, PI-3 kinase activation, calcium flux, and release of prostaglandin E2. In addition, GPR84 signaling in macrophages elicits Gi Gβγ-mediated augmentation of intracellular cAMP, rather than the decrease expected...Continue Reading

Citations

Feb 28, 2020·Cell Communication and Signaling : CCS·Anna PetersClaudia Stäubert
Sep 2, 2020·British Journal of Pharmacology·Sara MarsangoGraeme Milligan
Feb 14, 2019·Scientific Reports·Sarah J ManciniGraeme Milligan
Oct 24, 2019·Mini Reviews in Medicinal Chemistry·Zhaojun ShengWen-Hua Chen
Feb 14, 2021·International Journal of Molecular Sciences·Manuel GrundmannFrank Eitner
Dec 4, 2020·Journal of Medicinal Chemistry·Lin-Hai ChenFa-Jun Nan
Oct 19, 2021·ACS Pharmacology & Translational Science·Laura JenkinsGraeme Milligan

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