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, ATI and AT2. Each receptor subtype has been cloned and sequenced, with only 32% homol-ogy 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.
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