The Angiotensin Type 1 Receptor Activates Extracellular Signal‐Regulated Kinases 1 and 2 by G Protein‐Dependent and ‐Independent Pathways in Cardiac Myocytes and Langendorff‐Perfused Hearts

: The angiotensin II (AngII) type 1 receptor (AT1R) has been shown to activate extracellular signal‐regulated kinases 1 and 2 (ERK1/2) through G proteins or G protein‐independently through β‐arrestin2 in cellular expression systems. As activation mechanisms may greatly influence the biological effects of ERK1/2 activity, differential activation of the AT1R in its native cellular context could have important biological and pharmacological implications. To examine if AT1R activates ERK1/2 by G protein‐independent mechanisms in the heart, we used the [Sar1, Ile4, Ile8]‐AngII ([SII] AngII) analogue in native preparations of cardiac myocytes and beating hearts. We found that [SII] AngII does not activate Gq‐coupling, yet stimulates the β‐arrestin2‐dependent ERK1/2. The Gq‐activated pool of ERK1/2 rapidly translocates to the nucleus, while the β‐arrestin2‐scaffolded pool remains in the cytosol. Similar biased agonism was achieved in Langendorff‐perfused hearts, where both agonists elicit ERK1/2 phosphorylation, but [SII] AngII induces neither inotropic nor chronotropic effects.