Comparison of human ETA and ETB receptor signalling via G-protein and β-arrestin pathways

• DOI: 10.1016/j.lfs.2012.03.021
• Publication Date: 2012-03-27T04:43:19Z
• Authors: Janet J. Maguire; Rhoda E. Kuc; Victoria R. Pell; Andrew Green; Mike Brown; Sanj Kumar; Tom Wehrman; Elizabeth Quinn; Anthony P. Davenport
• Keywords: Arrestin; Affinities; Competitive antagonist

To determine the pharmacology of ETA- and ETB-mediated β-arrestin recruitment compare this to established human these receptors identify evidence for endothelin receptor biased signalling pathway specific blockade by antagonists. The ability ET-1, ET-2, ET-3, sarafotoxin 6b 6c activate ETA was determined in CHO-K1 cells. Affinities were obtained selective (BQ123, sitaxentan, ambrisentan), ETB (BQ788) mixed (bosentan) antagonists using ET-1 compared affinities competition experiments heart Schild analysis saphenous vein. Agonist dependence BQ123 BQ788 assays respectively. For recruitment, order potency as expected (ET-1 ≥ ET-2 >> ET-3) = receptors. However, at ET-3 partial agonists. Antagonism ET peptides appeared non-competitive. BQ123, but not BQ788, exhibited agonist-dependent affinities. Bosentan significantly more effective an inhibitor mediated receptor. In vasoconstrictor assay, S6b equipotent, full agonists tested behaved a competitive manner, although lower than predicted from binding left ventricle. These data suggest that linked G-protein- responses different bosentan show bias, preferentially blocking recruitment.