Author(s): Anthony L Albiston, Sharon G McDowall, Duana Matsacos
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.