The angiotensin type 1A receptor activates ERK1/2 via two independent pathways: a G protein-dependent pathway involving PKC and a G protein-independent pathway mediated by β-arrestin 2.
The study identifies distinct, independent G protein- and beta-arrestin 2-mediated pathways for ERK1/2 activation by the angiotensin type 1A receptor, implying distinct active receptor conformations.
Stimulation of a mutant angiotensin type 1A receptor (DRY/AAY) with angiotensin II (Ang II) or of a wild-type receptor with an Ang II analog (sarcosine1,Ile4,Ile8Ang II) fails to activate classical heterotrimeric G protein signaling but does lead to recruitment of beta-arrestin 2-GFP and activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) (maximum stimulation approximately 50% of wild type). This G protein-independent activation of mitogen-activated protein kinase is abolished by depletion of cellular beta-arrestin 2 but is unaffected by the PKC inhibitor Ro-31-8425. In parallel, stimulation of the wild-type angiotensin type 1A receptor with Ang II robustly stimulates ERK1/2 activation with approximately 60% of the response blocked by the PKC inhibitor (G protein dependent) and the rest of the response blocked by depletion of cellular beta-arrestin 2 by small interfering RNA (beta-arrestin dependent). These findings imply the existence of independent G protein- and beta-arrestin 2-mediated pathways leading to ERK1/2 activation and the existence of distinct "active" conformations of a seven-membrane-spanning receptor coupled to each.
Wei et al. (Fri,) reported a other. Angiotensin II and [Sar1,Ile4,Ile8]Ang II vs. Control siRNA or wild-type receptor was evaluated on ERK1/2 activation. The angiotensin type 1A receptor activates ERK1/2 via two independent pathways: a G protein-dependent pathway involving PKC and a G protein-independent pathway mediated by β-arrestin 2.