Dopamine Receptor D1 Is Exempt from Transforming Growth Factor #-Mediated Antifibrotic G Protein-Coupled Receptor Landscape Tampering in Lung FibroblastsS

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.