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 AT4 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 AT4receptor binding characteristics; the AT4 receptor ligands, angiotensin IV and LVV-hemorphin 7, compete for the binding of [125I]Nle1-angiotensin IV with IC50 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 AT4 receptor ligands may exert their effects by inhibiting the catalytic activity of IRAP thereby extending the half-life of its neuropeptide substrates.
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Published, JBC Papers in Press, November 13, 2001, DOI 10.1074/jbc.C100512200
This work was supported by a block grant from National Health and Medical Research Council of Australia (Reg Key Number 983001).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
