TY - JOUR
T1 - Dopamine Receptor D1 Is Exempt from Transforming Growth Factor b-Mediated Antifibrotic G Protein-Coupled Receptor Landscape Tampering in Lung Fibroblasts
AU - Gao, Ashley Y.
AU - Diaz Espinosa, Ana M.
AU - Nguyen, Ba Bao N.
AU - Link, Patrick A.
AU - Meridew, Jeffrey
AU - Jones, Dakota L.
AU - Gibbard, Daniel F.
AU - Tschumperlin, Daniel J.
AU - Haak, Andrew J.
N1 - Publisher Copyright:
Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.
PY - 2023/9/1
Y1 - 2023/9/1
N2 - Pulmonary fibroblasts are the primary producers of extracellular matrix (ECM) in the lungs, and their pathogenic activation drives scarring and loss of lung function in idiopathic pulmonary fibrosis (IPF). This uncontrolled production of ECM is stimulated by mechanosignaling and transforming growth factor beta 1 (TGF-b1) signaling that together promote transcriptional programs including Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). G protein-coupled receptors (GPCRs) that couple to G a s have emerged as pharmacological targets to inactivate YAP/TAZ signaling and promote lung fibrosis resolution. Previous studies have shown a loss of expression of “antifibrotic GPCRs”—receptors that couple to G a s, in IPF patient-derived fibroblasts compared with non-IPF samples. Of the 14 G a s GPCRs we found to be expressed in lung fibroblasts, the dopamine receptor D1 (DRD1) was one of only two not repressed by TGF-b1 signaling, with the b2-adrenergic receptor being the most repressed. We compared the potency and efficacy of multiple D1 and b2 receptor agonists 1/-TGF-b1 treatment in vitro for their ability to elevate cAMP, inhibit nuclear localization of YAP/TAZ, regulate expression of profibrotic and antifibrotic genes, and inhibit cellular proliferation and collagen deposition. Consistently, the activity of b2 receptor agonists was lost, whereas D1 receptor agonists was maintained, after stimulating cultured lung fibroblasts with TGF-b1. These data further support the therapeutic potential of the dopamine receptor D1 and highlight an orchestrated and pervasive loss of antifibrotic GPCRs mediated by TGF-b1 signaling.
AB - Pulmonary fibroblasts are the primary producers of extracellular matrix (ECM) in the lungs, and their pathogenic activation drives scarring and loss of lung function in idiopathic pulmonary fibrosis (IPF). This uncontrolled production of ECM is stimulated by mechanosignaling and transforming growth factor beta 1 (TGF-b1) signaling that together promote transcriptional programs including Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). G protein-coupled receptors (GPCRs) that couple to G a s have emerged as pharmacological targets to inactivate YAP/TAZ signaling and promote lung fibrosis resolution. Previous studies have shown a loss of expression of “antifibrotic GPCRs”—receptors that couple to G a s, in IPF patient-derived fibroblasts compared with non-IPF samples. Of the 14 G a s GPCRs we found to be expressed in lung fibroblasts, the dopamine receptor D1 (DRD1) was one of only two not repressed by TGF-b1 signaling, with the b2-adrenergic receptor being the most repressed. We compared the potency and efficacy of multiple D1 and b2 receptor agonists 1/-TGF-b1 treatment in vitro for their ability to elevate cAMP, inhibit nuclear localization of YAP/TAZ, regulate expression of profibrotic and antifibrotic genes, and inhibit cellular proliferation and collagen deposition. Consistently, the activity of b2 receptor agonists was lost, whereas D1 receptor agonists was maintained, after stimulating cultured lung fibroblasts with TGF-b1. These data further support the therapeutic potential of the dopamine receptor D1 and highlight an orchestrated and pervasive loss of antifibrotic GPCRs mediated by TGF-b1 signaling.
UR - http://www.scopus.com/inward/record.url?scp=85168238371&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85168238371&partnerID=8YFLogxK
U2 - 10.1124/jpet.122.001442
DO - 10.1124/jpet.122.001442
M3 - Article
C2 - 37024146
AN - SCOPUS:85168238371
SN - 0022-3565
VL - 386
SP - 277
EP - 287
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 3
ER -