GPCRs play pivotal roles in cellular sensing and intracellular responses to extracellular ligands. Protease-activated receptor 2 (PAR2) is a cell surface protein linked to G-protein dependent and independent intracellular signaling pathways that produce a wide range of physiological responses, including those related to metabolism, inflammation, pain, and cancer. PAR2 signaling pathways are involved in circulatory, cardiovascular, central nervous, gastrointestinal, metabolic, and respiratory systems. I-191 potently attenuated multiple PAR2-mediated intracellular signaling pathways leading to Ca2+ release, extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, Ras homologue gene family, member A (RhoA) activation, and inhibition of forskolin-induced cAMP accumulation. I-191 also potently inhibited PAR2-mediated downstream functional responses, including expression and secretion of inflammatory cytokines and cell apoptosis and migration, in human colon adenocarcinoma grade II cell line (HT29) and human breast adenocarcinoma cells (MDA-MB-231). In a cell study, I-191 inhibited intracellular Ca2+ release induced by either 2f-LIGRL-NH2 (pIC50 7.2 ± 0.1) or bovine trypsin (pIC50 6.7 ± 0.1) in HT29 cells and I-191 did not induce any agonist-induced calcium response at concentrations up to 100 μM. HT29 cells were treated with I-191 from 1 µM to 10 µM for 48h, the result showed that I-191 could inhibit PAR2-activated migration of HT29 cells, a property which can be associated with inhibition of PAR2-mediated signaling through ERK1/2 phosphorylation. The inhibitory effects of I-191 on PAR2-induced migration of MDA-MB-231 breast cancer cells are consistent with observations for HT29 colon cancer cells, indicating potent antagonist properties in different cancer cell lines. Unlike the biased ligand GB88, which does not inhibit ERK1/2 activation or PAR2-induced migration, I-191 strongly inhibited 2f-LIGRL-NH2–induced migration of MDA-MB-231 cells[1].
作用机制
I-191 acts in a concentration-dependent manner to displace a PAR2 ligand, 2f-LIGRLO-NH2, for binding to PAR2. I-191 had a surprisingly short residence time on PAR2 but was still able to attenuate calcium release induced by either a proteolytic (trypsin) or peptidic (2f-LIGRL-NH2) agonist of PAR2[1].
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