Angiotensin AT₄ ligands are potent, competitive inhibitors of insulin regulated aminopeptidase (IRAP)

Abstract

Angiotensin IV (Ang IV) exerts profound effects on memory and learning, a phenomenon ascribed to its binding to a specific AT 4 receptor. However the AT 4 receptor has recently been identified as the insulin-regulated aminopeptidase (IRAP). In this study, we demonstrate that AT 4 receptor ligands, including Ang IV, branes with high affinity, which was up to 200-fold greater than in the catalytic assay; this difference was not consistent among the peptides, and could not be ascribed to ligand degradation. Although some AT 4 ligands were subject to minor cleavage by HEK293T membranes, none were substrates for IRAP. Of a range of peptides tested, only vasopressin, oxytocin, and met-enkephalin were rapidly cleaved by IRAP. We propose that the physiological effects of AT 4 ligands result, in part, from inhibition of IRAP cleavage of neuropeptides involved in memory processing.

Alzheimer's, Angiotensin IV and an Aminopeptidase

“…20,34) Both Ang IV and LVV-H7 display competitive kinetics indicating that AT 4 ligands mediate their effects by binding to the catalytic site of IRAP. 27) Using the same system we also have demonstrated that although the peptides Ang IV and LVV-H7 bind to the catalytic stie they are not cleaved by IRAP. 27) Although IRAP was cloned nearly a decade ago, AT 4 ligands are the first high affinity inhibitors of the enzyme to be identified.…”

“…27) Using the same system we also have demonstrated that although the peptides Ang IV and LVV-H7 bind to the catalytic stie they are not cleaved by IRAP. 27) Although IRAP was cloned nearly a decade ago, AT 4 ligands are the first high affinity inhibitors of the enzyme to be identified. Development of stable, second generation inhibitors of IRAP based on the AT 4 ligands may provide the opportunity for the development of therapeutics for memory loss.…”

“…A number of studies have investigated the potential substrates of IRAP and have demonstrated that in vitro IRAP is capable of cleaving oxytocin, vasopressin, Metenkephalin, dynorphin A, Neurokinins A and B, somatostatin, CCK-8, and angiotensin III. [24][25][26][27] However, the physiological substrate remains unknown.…”

The Angiotensin IV Analog Nle-Tyr-Leu-ψ-(CH2-NH2)3-4-His-Pro-Phe (Norleual) Can Act as a Hepatocyte Growth Factor/c-Met Inhibitor

“…In this view, the multiple physiological actions of AngIV-related molecules are due to their ability to competitively inhibit IRAP, thus potentiating the actions of endogenous peptides that would normally be degraded by IRAP (Lew et al, 2003). However, there are several conceptual problems with this idea.…”

Cerebroprotective effects of RAS inhibitors: Beyond their cardio-renal actions

“…angiotensin AT4 ligand (Ang IV) and insulin-regulated aminopeptidase. 16 The regional distribution of angiotensin receptor subtypes in the central nervous subtypes is shown in Table 1.…”