What’s new in the renin-angiotensin system?
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The angiotensin AT4 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 AT4 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 AT4 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 AT4 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 AT4 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.
- What’s new in the renin-angiotensin system?
Cellular and Molecular Life Sciences CMLS
Volume 61, Issue 21 , pp 2728-2737
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- Insulin-regulated aminopeptidase
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- Author Affiliations
- 1. Neurochemistry, Howard Florey Institute, The University of Melbourne, Parkville, Victoria, 3010, Australia
- 2. Department of Anatomy and Cell Biology, The University of Melbourne, Parkville, Victoria, 3010, Australia
- 3. Department of Genetics, The University of Melbourne, Parkville, Victoria, 3010, Australia
- 4. Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, 3010, Australia
- 5. Department of Biochemistry, The University of Melbourne, Parkville, Victoria, 3010, Australia