Angiotensin AT4 ligands are potent, competitive inhibitors of insulin regulated aminopeptidase (IRAP)

Lew, Rebecca A., Mustafa, Tomris, Ye, Siying, McDowall, Sharon G., Chai, Siew Yeen and Albiston, Anthony L. 2003, Angiotensin AT4 ligands are potent, competitive inhibitors of insulin regulated aminopeptidase (IRAP), Journal of neurochemistry, vol. 86, no. 2, pp. 344-350, doi: 10.1046/j.1471-4159.2003.01852.x.

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Title Angiotensin AT4 ligands are potent, competitive inhibitors of insulin regulated aminopeptidase (IRAP)
Author(s) Lew, Rebecca A.
Mustafa, Tomris
Ye, SiyingORCID iD for Ye, Siying
McDowall, Sharon G.
Chai, Siew Yeen
Albiston, Anthony L.
Journal name Journal of neurochemistry
Volume number 86
Issue number 2
Start page 344
End page 350
Total pages 7
Publisher Wiley - Blackwell Publishing
Place of publication Chichester, England
Publication date 2003-07
ISSN 0022-3042
Keyword(s) Ang IV
AT4 receptor
enzyme kinetics
Summary Angiotensin IV (Ang IV) exerts profound effects on memory and learning, a phenomenon ascribed to its binding to a specific AT4 receptor. However the AT4 receptor has recently been identified as the insulin-regulated aminopeptidase (IRAP). In this study, we demonstrate that AT4 receptor ligands, including Ang IV, Nle1-Ang IV, divalinal-Ang IV, and the structurally unrelated LVV-hemorphin-7, are all potent inhibitors of IRAP catalytic activity, as assessed by cleavage of leu-β-naphthylamide by recombinant human IRAP. Both Ang IV and divalinal–Ang IV display competitive kinetics, indicating that AT4 ligands mediate their effects by binding to the catalytic site of IRAP. The AT4 ligands also displaced [125I]-Nle1-Ang IV or [125I]-divalinal1-Ang IV from IRAP-HEK293T membranes with high affinity, which was up to 200-fold greater than in the catalytic assay; this difference was not consistent among the peptides, and could not be ascribed to ligand degradation. Although some AT4 ligands were subject to minor cleavage by HEK293T membranes, none were substrates for IRAP. Of a range of peptides tested, only vasopressin, oxytocin, and met-enkephalin were rapidly cleaved by IRAP. We propose that the physiological effects of AT4 ligands result, in part, from inhibition of IRAP cleavage of neuropeptides involved in memory processing.
Language eng
DOI 10.1046/j.1471-4159.2003.01852.x
Field of Research 119999 Medical and Health Sciences not elsewhere classified
Socio Economic Objective 970111 Expanding Knowledge in the Medical and Health Sciences
HERDC Research category C1.1 Refereed article in a scholarly journal
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Document type: Journal Article
Collection: School of Medicine
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