The human angiotensin AT1 receptor supports G protein-independent extracellular signal-regulated kinase 1/2 activation and cellular proliferation

The angiotensin AT1 receptor is a key regulator of blood pressure and body fluid homeostasis, and it plays a key role in the pathophysiology of several cardiovascular diseases such as hypertension, cardiac hypertrophy, congestive heart failure, and arrhythmia. The importance of human angiotensin AT1 receptor signalling is illustrated by the common use of angiotensin AT1 receptor-inverse agonists in clinical practice. It is well established that rodent orthologues of the angiotensin AT1 receptor can selectively signal through G protein-dependent and -independent mechanisms in recombinant expression systems, primary cells and in vivo. The in vivo work clearly demonstrates profoundly different cellular consequences of angiotensin AT1 receptor signalling in the cardiovascular system, suggesting pharmacological potential for drugs which specifically affect a subset of angiotensin AT1 receptor actions. However, it is currently unknown whether the human angiotensin AT1 receptor can signal through G protein-independent mechanisms — and if so, what the physiological impact of such signalling is. We have performed a detailed pharmacological analysis of the human angiotensin AT1 receptor using a battery of angiotensin analogues and registered drugs targeting this receptor. We show that the human angiotensin AT1 receptor signals directly through G protein-independent pathways and supports NIH3T3 cellular proliferation. The realization of G protein-independent signalling by the human angiotensin AT1 receptor has clear pharmacological implications for development of drugs with pathway-specific actions and defined biological outcomes.