Angiotensin AT4 ligands are potent, competitive inhibitors of insulin regulated aminopeptidase (IRAP)
Angiotensin AT4 ligands are potent, competitive inhibitors of insulin regulated aminopeptidase (IRAP)
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DOI：
10.1046/j.1471-4159.2003.01852.x
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发表时间：
2003-07-01
影响因子：
4.7
通讯作者：
Albiston, AL
中科院分区：
文献类型：
--
作者：
Lew, RA;Mustafa, T;Albiston, AL
血管紧张素IV （angiv）对记忆和学习具有深远的影响，这一现象归因于其与特定AT(4)受体的结合。然而，AT(4)受体最近被确定为胰岛素调节的氨基肽酶（IRAP）。在这项研究中，我们证明AT(4)受体配体，包括Ang IV， Nle(1) -Ang IV, divalinal-Ang IV，以及结构无关的LVV-hemorphin-7，都是IRAP催化活性的有效抑制剂，通过重组人IRAP裂解亮氨酸- β -萘酰胺来评估。Ang IV和divalinal-Ang IV均表现出竞争动力学，表明AT(4)配体通过结合IRAP的催化位点介导其作用。AT(4)配体也以高亲和力从IRAP-HEK293T膜上取代[(125)I]-Nle(1) -Ang IV或[(125)I]-divalinal1-Ang IV，其亲和力比催化实验高200倍；这种差异在多肽之间并不一致，不能归因于配体降解。虽然一些AT(4)配体受到HEK293T膜的轻微切割，但没有一个是IRAP的底物。在一系列测试的肽中，只有抗利尿激素、催产素和脑啡肽能被IRAP快速切割。我们认为AT(4)配体的生理作用部分是由于抑制IRAP切割参与记忆加工的神经肽。
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, Nle(1) -Ang IV, divalinal-Ang IV, and the structurally unrelated LVV-hemorphin-7, are all potent inhibitors of IRAP catalytic activity, as assessed by cleavage of leu-beta-naphthylamide by recombinant human IRAP. Both Ang IV and divalinal-Ang IV display competitive kinetics, indicating that AT(4) ligands mediate their effects by binding to the catalytic site of IRAP. The AT(4) ligands also displaced [(125) I]-Nle(1) -Ang IV or [(125) I]-divalinal1-Ang IV from IRAP-HEK293T membranes 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.