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

摘要: article i nfo Article history: Received 2 November 2011 Accepted 8 March 2012 Aims: 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 sig- nalling pathway specific blockade by antagonists. Main methods: The ability ET-1, ET-2, ET-3, sarafotoxin 6b 6c activate ETA ETB- mediated 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. Key findings: For recruitment, order potency as expected (ET-1 ≥ET-2>>ET-3) (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 receptor. In vasoconstrictor assay, ET-2 S6b equipotent, full agonists tested behaved a competitive manner, although lower than predicted from binding left ventricle. Significance: These data suggest that linked G-protein- β- arrestin responses different bosentan show bias, preferentially blocking recruitment.