The
angiotensin AT(1) 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 AT(1) receptor signalling is illustrated by the common use of
angiotensin AT(1) receptor-inverse agonists in clinical practice. It is well established that rodent orthologues of the
angiotensin AT(1) 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 AT(1) receptor signalling in the cardiovascular system, suggesting pharmacological potential for drugs which specifically affect a subset of
angiotensin AT(1) receptor actions. However, it is currently unknown whether the human
angiotensin AT(1) 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 AT(1) receptor using a battery of
angiotensin analogues and registered drugs targeting this receptor. We show that the human
angiotensin AT(1) receptor signals directly through
G protein-independent pathways and supports NIH3T3 cellular proliferation. The realization of
G protein-independent signalling by the human
angiotensin AT(1) receptor has clear pharmacological implications for development of drugs with pathway-specific actions and defined biological outcomes.