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

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, incl...

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Vydáno v:	Journal of neurochemistry Ročník 86; číslo 2; s. 344 - 350
Hlavní autoři:	Lew, Rebecca A., Mustafa, Tomris, Ye, Siying, McDowall, Sharon G., Chai, Siew Yeen, Albiston, Anthony L.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	Oxford, UK Blackwell Science Ltd 01.07.2003 Blackwell
Témata:	Aminopeptidases - antagonists & inhibitors Aminopeptidases - chemistry Aminopeptidases - metabolism Ang IV Angiotensin II - analogs & derivatives Angiotensin II - pharmacology Angiotensin Receptor Antagonists AT4 receptor Binding, Competitive - drug effects Biological and medical sciences Cell Line Cell receptors Cell structures and functions Cystinyl Aminopeptidase Enzyme Activation - drug effects Enzyme Inhibitors - pharmacology enzyme kinetics Fundamental and applied biological sciences. Psychology Hemoglobins - pharmacology hemorphin Humans Kidney - cytology Kidney - metabolism Leucine - analogs & derivatives Leucine - metabolism Ligands Miscellaneous Molecular and cellular biology Oligopeptides - pharmacology Peptide Fragments - pharmacology Peptides - chemistry Peptides - metabolism Receptors, Angiotensin - chemistry Receptors, Angiotensin - metabolism Recombinant Proteins Substrate Specificity - physiology Ligand binding Enzyme Aminopeptidases Binding site Angiotensin receptor Angiotensin IV Gene expression enzyme kinetics Peptidases Renin angiotensin system Cell line Proteolysis AT4 receptor Angiotensin Hydrolases AT4 angiotensin receptor Kinetics Ang IV hemorphin
ISSN:	0022-3042, 1471-4159
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-3042 1471-4159
DOI:	10.1046/j.1471-4159.2003.01852.x