The angiotensin IV/AT4 receptor

• Published in: Cellular and molecular life sciences : CMLS Vol. 61; no. 21; pp. 2728 - 2737
• Main Authors: Chai, S Y, Fernando, R, Peck, G, Ye, S-Y, Mendelsohn, F A O, Jenkins, T A, Albiston, A L
• Format: Journal Article
• Language: English
• Published: Switzerland 01.11.2004
• Subjects: Aminopeptidases - metabolism; Angiotensin II - analogs & derivatives; Angiotensin II - metabolism; Angiotensin Receptor Antagonists; Animals; Cystinyl Aminopeptidase; Glucose - metabolism; Humans; Memory - physiology; Receptors, Angiotensin - agonists; Receptors, Angiotensin - metabolism; Signal Transduction
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-004-4246-1

The angiotensin AT(4) receptor was originally defined as the specific, high-affinity binding site for the hexapeptide angiotensin IV (Ang IV). Subsequently, the peptide LVV-hemorphin 7 was also demonstrated to be a bioactive ligand of the AT(4) receptor. Central administration of Ang IV, its analogues or LVV-hemorphin 7 markedly enhance learning and memory in normal rodents and reverse memory deficits observed in animal models of amnesia. The AT(4) receptor has a broad distribution and is found in a range of tissues, including the adrenal gland, kidney, lung and heart. In the kidney Ang IV increases renal cortical blood flow and decreases Na(+) transport in isolated renal proximal tubules. The AT(4) receptor has recently been identified as the transmembrane enzyme, insulin-regulated membrane aminopeptidase (IRAP). IRAP is a type II integral membrane spanning protein belonging to the M1 family of aminopeptidases and is predominantly found in GLUT4 vesicles in insulin-responsive cells. Three hypotheses for the memory-potentiating effects of the AT(4) receptor/IRAP ligands, Ang IV and LVV-hemorphin 7, are proposed: (i) acting as potent inhibitors of IRAP, they may prolong the action of endogenous promnestic peptides; (ii) they may modulate glucose uptake by modulating trafficking of GLUT4; (iii) IRAP may act as a receptor, transducing the signal initiated by ligand binding to its C-terminal domain to the intracellular domain that interacts with several cytoplasmic proteins.