Abstract
The octapeptide angiotensin II (AngII) exerts a variety of cardiovascular effects through the activation of the AngII type 1 receptor (AT1), a G protein-coupled receptor. The AT1 receptor engages and activates several signalling pathways, including heterotrimeric G proteins Gq and G12, as well as the ERK1/2 pathway. Additionally, following stimulation, β-arrestin is recruited to the AT1 receptor, leading to receptor desensitization. It is increasingly recognized that specific ligands selectively bind and favour the activation of some signalling pathways over others, a concept termed ligand bias or functional selectivity. A better understanding of the molecular basis of functional selectivity may lead to the development of better therapeutics with fewer adverse effects. In the present study, we developed assays allowing the measurement of 6 different signalling modalities of the AT1 receptor. Using a series of AngII peptide analogs that were modified in positions 1, 4 and 8, we sought to better characterize the molecular determinants of AngII that underlie functional selectivity of the AT1 receptor in HEK293 cells. The results reveal that position 1 of AngII does not confer functional selectivity, while position 4 confers a bias towards ERK signalling over Gq signalling and that position 8 confers a bias towards β-arrestin recruitment over ERK activation and Gq signalling. Interestingly, the analogs modified in position 8 were also partial agonists of the PKC-dependent ERK pathway via atypical PKC isoforms PKCζ and PKCι.
- The American Society for Pharmacology and Experimental Therapeutics