Angiotensin IV binding site - The AT4 receptor or insulin regulated aminopeptidase (IRAP)

Angiotensin IV (Ang IV) is a hexapeptide fragment corresponding to amino acids 3-8 (VYIHPF) of angiotensin II (Ang II) that is formed by consecutive actions of aminopeptidase A and aminopeptidase N (1) (Fig. 1). Ang IV acts as a weak agonist at the Ang II AT1 receptor, and was generally believed to have no physiological role because of its ineffectiveness in the regulation of blood pressure, fluid balance, or adrenal steroid secretion. However, in 1988, specific actions were discovered for Ang IV in the brain-the peptide was found to facilitate memory retention and retrieval (2). A specific, high-affinity binding site was subsequently described in bovine adrenal membranes, which bound Ang IV saturably, reversibly, and with nanomolar affinity (3,4). This binding site was termed as the angiotensin AT4 receptor by an IUPHAR nomenclature committee (5). This AT4 receptor site is pharmacologically distinct from both Ang II AT1 and AT2 receptors, and bound Ang II at only micromolar affinity.