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 (AT ₁R) 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 AT ₁R in its native cellular context could have important biological and pharmacological implications. To examine if AT ₁R activates ERK1/2 by G protein-independent mechanisms in the heart, we used the [Sar ¹, Ile ⁴, Ile ⁸]-AngII ([SII] AngII) analogue in native preparations of cardiac myocytes and beating hearts. We found that [SII] AngII does not activate G _q-coupling, yet stimulates the β-arrestin2-dependent ERK1/2. The G _q-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.