At4 receptor is insulinregulated aminopeptidase

We have purified the AT4 receptor from bovine adrenal membranes and identified it as insulin-regulated aminopeptidase (IRAP) (11). To verify that the AT4 receptor is indeed identical to IRAP, we sought to (1) reconstitute 125I-[Nle1]Ang IV binding site and investigate its biochemical properties by expression of IRAP cDNA, and (2) compare the distribution of the 125I-[Nle1]Ang IV binding in brain with IRAP mRNA and protein expression. Using HEK 293T cells transfected with the full-length cDNA for human IRAP, we observed abundant high-affinity binding for 125I-[Nle1]Ang IV with a pharmacological profile identical to the endogenous human AT4 receptor (12). In addition, membranes from cells transfected with human IRAP crosslinked with a radiolabeled analog of Ang IV expressed a major band at 165 kDa, which was displaced by 1 pMAng IV and is identical with our previous characterization of the native AT4 receptor (11,12). Cellular expression of both IRAP mRNA and protein closely paralleled the distribution of the AT4 receptor in brain (11) (Fig. 2). We have therefore conclusively demonstrated that the specific high-affinity binding site for Ang IV/AT4 receptor is the enzyme IRAP.

IRAP was described as an aminopeptidase colocalized in specialized intracellular vesicles with the glucose transporter, GLUT4, in insulin-responsive tissues, adipose, skeletal muscle, and cardiac muscle (13). IRAP is a member of the M1 family of the zinc-dependent metallopeptidases, and is also known as placental leucine aminopeptidase (P-LAP), or oxytocinase (14).

This review focuses on the IRAP/AT4 receptor distribution and function in the cardiovascular system and brain. The AT4 receptor was first described in bovine adrenal membranes (3). Subsequently, it was shown to be widely distributed in many tissues including kidney, heart, spleen and brain in a number of different species. Although this protein was known as (1) the AT4 receptor/125I-Ang IV binding site (in most of the literature published about the kidney, adrenal, cardiovascular, and central nervous systems prior to 2002), (2) IRAP/vp165 (in insulin-responsive tissues), or (3) oxytocinase/ P-LAP (in the placenta), in this review the protein will be referred to in the historical context according to the name given in the published literature.

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