Evidence That the Angiotensin IV (AT4) Receptor Is the Enzyme Insulin-regulated Aminopeptidase

Anthony L. Albiston, Sharon G. McDowall, Duana Matsacos, Pamela Sim, Eleanor Clune, Tomris Mustafa, Joohyung Lee, Frederick A O Mendelsohn, Richard J. Simpson, Lisa M. Connolly, Siew Yeen Chai

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Central infusion of angiotensin IV or its more stable analogues facilitates memory retention and retrieval in normal animals and reverses amnesia induced by scopolamine or by bilateral perforant pathway lesions. These peptides bind with high affinity and specificity to a novel binding site designated the angiotensin AT4 receptor. Until now, the AT 4 receptor has eluded molecular characterization. Here we identify the AT4 receptor, by protein purification and peptide sequencing, to be insulin-regulated aminopeptidase (IRAP). HEK 293T cells transfected with IRAP exhibit typical AT4 receptor binding characteristics; the AT4 receptor ligands, angiotensin IV and LVV-hemorphin 7, compete for the binding of [125I]Nle1-angiotensin IV with IC 50 values of 32 and 140 nM, respectively. The distribution of IRAP and its mRNA in the brain, determined by immunohistochemistry and hybridization histochemistry, parallels that of the AT4 receptor determined by radioligand binding. We also show that AT4 receptor ligands dose-dependently inhibit the catalytic activity of IRAP. We have therefore demonstrated that the AT4 receptor is IRAP and propose that AT 4 receptor ligands may exert their effects by inhibiting the catalytic activity of IRAP thereby extending the half-life of its neuropeptide substrates.

Original languageEnglish
Pages (from-to)48623-48626
Number of pages4
JournalJournal of Biological Chemistry
Issue number52
Publication statusPublished - 28 Dec 2001
Externally publishedYes

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