Journal article
Dopamine Receptor D1 Is Exempt from Transforming Growth Factor #-Mediated Antifibrotic G Protein-Coupled Receptor Landscape Tampering in Lung FibroblastsS
The Journal of pharmacology and experimental therapeutics, Vol.386(3), pp.277-287
09/01/2023
DOI: 10.1124/jpet.122.001442
PMCID: PMC10449101
PMID: 37024146
Abstract
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-#1) 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. Previ-ous 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-#1 signaling, with the #2-adrenergic receptor being the most re-pressed. We compared the potency and efficacy of multiple D1 and #2 receptor agonists 1/- TGF-#1 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. Consis-tently, the activity of #2 receptor agonists was lost, whereas D1 receptor agonists was maintained, after stimulating cultured lung fibroblasts with TGF-#1. 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-#1 signaling.
Details
- Title: Subtitle
- Dopamine Receptor D1 Is Exempt from Transforming Growth Factor #-Mediated Antifibrotic G Protein-Coupled Receptor Landscape Tampering in Lung FibroblastsS
- Creators
- Ashley Y. Gao - WinnMedAna M. Diaz Espinosa - WinnMedBa Bao N. Nguyen - WinnMedPatrick A. Link - WinnMedJeffrey Meridew - WinnMedDakota L. Jones - WinnMedDaniel F. Gibbard - WinnMedDaniel J. Tschumperlin - WinnMedAndrew J. Haak - WinnMed
- Resource Type
- Journal article
- Publication Details
- The Journal of pharmacology and experimental therapeutics, Vol.386(3), pp.277-287
- DOI
- 10.1124/jpet.122.001442
- PMID
- 37024146
- PMCID
- PMC10449101
- NLM abbreviation
- J Pharmacol Exp Ther
- ISSN
- 0022-3565
- eISSN
- 1521-0103
- Publisher
- Elsevier
- Number of pages
- 11
- Grant note
- Brewer Family Career Development Award in Support of Idiopathic Pulmonary Fibrosis and Related Interstitial Lung Disease Research (Mayo Clinic) Pulmonary Fibrosis Scholar Award Boehringer Ingelheim Discovery Award; Boehringer Ingelheim 1R61-HL161804; 5R01-HL092961 / National Institutes of Health National Heart, Lung, and Blood Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) American Lung Association Catalyst Award
- Language
- English
- Date published
- 09/01/2023
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Anatomy and Cell Biology; Craniofacial Anomalies Research Center
- Record Identifier
- 9984948045102771
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