The angiotensin IV/AT4 receptor.
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.
Chai
S Y
SY
Neurochemistry, Howard Florey Institute, The University of Melbourne, Parkville, Victoria 3010, Australia. sychai@hfi.unimelb.edu.au.
Fernando
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R
Peck
G
G
Ye
S-Y
SY
Mendelsohn
F A O
FA
Jenkins
T A
TA
Albiston
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AL
D000626:Aminopeptidases / Q000378:metabolism; D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D010122:Cystinyl Aminopeptidase; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008568:Memory / Q000502:physiology; D011945:Receptors, Angiotensin / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction
C090830:AT4 receptor; D057911:Angiotensin Receptor Antagonists; D011945:Receptors, Angiotensin; D000804:Angiotensin II; C012877:angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-; D000626:Aminopeptidases; D010122:Cystinyl Aminopeptidase; C105964:leucyl-cystinyl aminopeptidase; D005947:Glucose