Evidence that the angiotensin IV (AT(4)) receptor is the enzyme insulin-regulated aminopeptidase

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 designate...

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Vydané v:	The Journal of biological chemistry Ročník 276; číslo 52; s. 48623
Hlavní autori:	Albiston, A L, McDowall, S G, Matsacos, D, Sim, P, Clune, E, Mustafa, T, Lee, J, Mendelsohn, F A, Simpson, R J, Connolly, L M, Chai, S Y
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 28.12.2001
Predmet:	Aminopeptidases - antagonists & inhibitors Aminopeptidases - genetics Aminopeptidases - isolation & purification Aminopeptidases - metabolism Angiotensin II - analogs & derivatives Angiotensin II - chemistry Angiotensin II - metabolism Angiotensin Receptor Antagonists Animals Autoradiography Brain - cytology Brain - enzymology Brain - metabolism Cell Line Cystinyl Aminopeptidase Hemoglobins - metabolism Humans Immunohistochemistry In Situ Hybridization Iodine Radioisotopes - chemistry Iodine Radioisotopes - metabolism Mice Mice, Inbred C57BL Peptide Fragments - metabolism Radioligand Assay Receptors, Angiotensin - genetics Receptors, Angiotensin - isolation & purification Receptors, Angiotensin - metabolism Recombinant Fusion Proteins - metabolism Transfection
ISSN:	0021-9258
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Shrnutí:	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 AT(4) receptor. Until now, the AT(4) receptor has eluded molecular characterization. Here we identify the AT(4) receptor, by protein purification and peptide sequencing, to be insulin-regulated aminopeptidase (IRAP). HEK 293T cells transfected with IRAP exhibit typical AT(4) receptor binding characteristics; the AT(4) receptor ligands, angiotensin IV and LVV-hemorphin 7, compete for the binding of [(125)I]Nle(1)-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 AT(4) receptor determined by radioligand binding. We also show that AT(4) receptor ligands dose-dependently inhibit the catalytic activity of IRAP. We have therefore demonstrated that the AT(4) 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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0021-9258
DOI:	10.1074/jbc.C100512200