Abstract

The cardiovascular and other actions of angiotensin II (Ang II) are mediated by AT₁ and AT₂ receptors, which are seven transmembrane glycoproteins with 30% sequence similarity. Most species express a single autosomal AT₁ gene, but two related AT_1A and AT_1B receptor genes are expressed in rodents. AT₁ receptors are predominantly coupled to G_q/11, and signal through phospholipases A, C, D, inositol phosphates, calcium channels, and a variety of serine/threonine and tyrosine kinases. Many AT₁-induced growth responses are mediated by transactivation of growth factor receptors. The receptor binding sites for agonist and nonpeptide antagonist ligands have been defined. The latter compounds are as effective as angiotensin converting enzyme inhibitors in cardiovascular diseases but are better tolerated. The AT₂receptor is expressed at high density during fetal development. It is much less abundant in adult tissues and is up-regulated in pathological conditions. Its signaling pathways include serine and tyrosine phosphatases, phospholipase A₂, nitric oxide, and cyclic guanosine monophosphate. The AT₂ receptor counteracts several of the growth responses initiated by the AT₁ and growth factor receptors. The AT₄ receptor specifically binds Ang IV (Ang 3–8), and is located in brain and kidney. Its signaling mechanisms are unknown, but it influences local blood flow and is associated with cognitive processes and sensory and motor functions. Although AT₁ receptors mediate most of the known actions of Ang II, the AT₂ receptor contributes to the regulation of blood pressure and renal function. The development of specific nonpeptide receptor antagonists has led to major advances in the physiology, pharmacology, and therapy of the renin-angiotensin system.