(maximum stimulation Ϸ50% of wild type). This G protein-independent activation of mitogen-activated protein kinase is abolished by depletion of cellular ␤-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 ERK1͞2 activation with Ϸ60% of the response blocked by the PKC inhibitor (G protein dependent) and the rest of the response blocked by depletion of cellular ␤-arrestin 2 by small interfering RNA (␤-arrestin dependent). These findings imply the existence of independent G protein-and ␤-arrestin 2-mediated pathways leading to ERK1͞2 activation and the existence of distinct ''active'' conformations of a seven-membrane-spanning receptor coupled to each.