In 1988, a series of reports described the ability of imidazole
acetic acid derivatives to act as antagonists at the
angiotensin receptor.During the course of characterization
of these compounds, it became apparent that certain
tissues contained different subtypes of angiotensin
receptors. Angiotensin receptors have been classified
into two subtypes,AT1 and AT2. Each receptor subtype
has been cloned and sequenced, with only 32% homology
in the protein sequences for the two receptors. The
AT1 receptor uses G proteins as signal transducers and
is coupled through traditional second-messenger systems
that involve phospholipase C and calcium mobilization,
inhibition of adenylyl cyclase, stimulation of
mitogen-activated protein kinases and the JAK/STAT
pathway, and activation of Jun-kinase. In contrast, the
signaling cascades of the AT2 receptor involve the activation
of phosphorylases, which inhibit phosphorylation
steps of certain types of cell growth.
The distribution of the AT1 and AT2 receptor subtypes
is species and tissue specific. The major biological
functions of angiotensin II (cardiovascular regulation)
are mediated through the ATI receptor. In contrast, despite
the increased presence of AT2 receptors in fetal
tissues, a lack of AT2 receptors appears to be compatible
with life. Current evidence suggests that in general,
stimulation of the AT2 receptor appears to oppose
those physiological actions of angiotensin II that are
mediated through the AT1 receptor.
Angiotensin IV, the smallest bioactive peptide product
of the renin–angiotensin system, interacts with a
unique receptor termed the angiotensin IV receptor; this
receptor exhibits minimal affinity for angiotensin II or
angiotensin III.
