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Review
. 2020 Mar;41(3):172-182.
doi: 10.1016/j.tips.2019.12.008. Epub 2020 Jan 30.

Targeting GPCR Signaling for Idiopathic Pulmonary Fibrosis Therapies

Andrew J Haak  1 , Merrick T Ducharme  2 , Ana M Diaz Espinosa  2 , Daniel J Tschumperlin  2
Affiliations
Review

Targeting GPCR Signaling for Idiopathic Pulmonary Fibrosis Therapies

Andrew J Haak et al. Trends Pharmacol Sci. 2020 Mar.

Abstract

A variety of G protein-coupled receptors (GPCRs) have been implicated in the pathogenesis of pulmonary fibrosis, largely through their promotion of profibrotic fibroblast activation. By contrast, recent work has highlighted the beneficial effects of Gαs-coupled GPCRs on reducing fibroblast activation and fibrosis. This review highlights how fibrosis-promoting and -inhibiting GPCR signaling converges on downstream signaling and transcriptional effectors, and how the diversity and dynamics of GPCR expression challenge efforts to identify effective therapies for idiopathic pulmonary fibrosis (IPF). Next-generation strategies to overcome these challenges, focusing on target selection, polypharmacology, and personalized medicine approaches, are discussed as a path towards more effective GPCR-targeted therapies for pulmonary fibrosis.

Keywords: G protein-coupled receptor; MRTF; ROCK; TAZ; YAP; fibrosis.

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Figures

Fig. 1.
Fig. 1.. GPCR Signaling Promotes profibrotic and antifibrotic signaling.
In IPF there is increased abundance of profibrotic ligands, notably: LPA, endothelin, and serotonin that activate receptors coupled to Gαi/o, Gαq/11, Gα12/13 promoting multiple pathways including Rho and ROCK which regulates the actin cytoskeleton. MRTF-A/B and YAP/TAZ are cytoskeletal sensitive profibrotic transcription co-factors essential to fibroblast activation. Known transcript targets for MRTF and YAP/TAZ are profibrotic genes: COL1A1, COL1A2, CTGF,and ACTA2. GPCRs which couple to Gαs are antifibrotic and negatively regulate MRTF-A/B and YAP/TAZ, but are often repressed in IPF patient fibroblasts. Profibrotic signaling is shown in orange and antifibrotic signaling is show in blue.
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