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PEPTIDE LIGAND C391 AS A POTENTIAL PAR‐2 β‐ARRESTIN BIASED ANTAGONIST
Author(s) -
Ming Monica,
Yee Michael C,
Lee Kyu J,
Siegler Michael D.,
Arrellano Marisol,
Aghayan Sara,
DeFea Kathryn
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.644.13
Subject(s) - proteases , chemistry , antagonist , arrestin , protease activated receptor 2 , receptor , microbiology and biotechnology , pharmacology , g protein coupled receptor , biology , biochemistry , enzyme , enzyme linked receptor
Protease Activated Receptor‐2 (PAR‐2) promotes two independent and opposing pathways: G‐alpha‐q (G αq ), and β‐arrestin. Studies characterizing the role of PAR‐2 in airway inflammation have shown that the G αq pathway has protective effects by the release of prostaglandin E 2 (PGE2), leading to bronchodilation. And that the β‐arrestin pathway has pro‐inflammatory effects through leukocyte infiltration into the lungs, epithelial thickening, and mucus production. These conflicting views led us to investigate whether a biased antagonist of PAR‐2, that preferentially silences β‐arrestin signaling, may also inhibit the inflammatory effects of allergenic proteases in the airway. Recent studies have identified a number of new, high affinity agonists and antagonists of PAR2. One of the peptide ligands found was C391, which was shown to be a weak agonist and antagonist of PAR‐2, however it was only tested for calcium (Ca 2+ ) mobilization. Preliminary results from our lab suggest that C391 affects β‐arrestin‐2 recruitment to PAR‐2 at a lower concentration than it affects Ca 2+ mobilization, suggesting it is a good candidate for a biased PAR‐2 antagonist. Using bioluminescent resonance energy transfer methods and protein analysis, this study demonstrates that C391 can affect both cofilin (an actin severing protein) dephosphorylation and β‐arrestin recruitment –elicited by trypsin and allergenic proteases from Alternaria Alternata and cockroach extracts in a dose dependent response– at concentrations where it does not affect Ca 2+ mobilization or phosphatidylinositide 3‐kinase (PI3K) activation.