The angiotensin IV/AT4 receptor

Cell Mol Life Sci. 2004 Nov;61(21):2728-37. 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.

Publication types

  • Review

MeSH terms

  • 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


  • AT4 receptor
  • Angiotensin Receptor Antagonists
  • Receptors, Angiotensin
  • Angiotensin II
  • angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-
  • Aminopeptidases
  • Cystinyl Aminopeptidase
  • leucyl-cystinyl aminopeptidase
  • Glucose