International union of pharmacology. XXIII. The angiotensin II receptors

The cardiovascular and other actions of angiotensin II (Ang II) are mediate d by AT(1) and AT(2) receptors, which are seven transmembrane glycoproteins with 30% sequence similarity. Most species express a single autosomal AT(1 ) gene, but two related AT(1A) and AT(1B) receptor genes are expressed in r odents. AT(1) receptors are predominantly coupled to G(q/11), and signal th rough phospholipases A, C, D, inositol phosphates, calcium channels, and a variety of serine/threonine and tyrosine kinases. Many AT(1)-induced growth responses are mediated by transactivation of growth factor receptors. The receptor binding sites for agonist and nonpeptide antagonist ligands have b een defined. The latter compounds are as effective as angiotensin convertin g enzyme inhibitors in cardiovascular diseases but are better tolerated. Th e AT(2) receptor 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 A(2), nitric oxide, and cyclic guanosine monophosphate. The AT(2) receptor counteracts several of the growth responses initiated by th e AT(1) and growth factor receptors. The AT(4) receptor specifically binds Ang IV (Ang 3-8), and is located in brain and kidney. Its signaling mechani sms are unknown, but it influences local blood flow and is associated with cognitive processes and sensory and motor functions. Although AT(1) recepto rs mediate most of the known actions of Ang II, the AT(2) receptor contribu tes to the regulation of blood pressure and renal function. The development of specific nonpeptide receptor antagonists has led to major advances in t he physiology, pharmacology, and therapy of the renin-angiotensin system.