Chai S Y, Fernando R, Peck G, Ye S-Y, Mendelsohn F A O, Jenkins T A, Albiston A L
Neurochemistry, Howard Florey Institute, The University of Melbourne, Parkville, Victoria 3010, Australia.
Cell Mol Life Sci. 2004 Nov;61(21):2728-37. doi: 10.1007/s00018-004-4246-1.
The angiotensin AT(4) receptor was originally defined as the specific, high-affinity binding site for the hexapeptide angiotensin IV (Ang IV). Subsequently, the peptide LVV-hemorphin 7 was also demonstrated to be a bioactive ligand of the AT(4) receptor. Central administration of Ang IV, its analogues or LVV-hemorphin 7 markedly enhance learning and memory in normal rodents and reverse memory deficits observed in animal models of amnesia. The AT(4) receptor has a broad distribution and is found in a range of tissues, including the adrenal gland, kidney, lung and heart. In the kidney Ang IV increases renal cortical blood flow and decreases Na(+) transport in isolated renal proximal tubules. The AT(4) receptor has recently been identified as the transmembrane enzyme, insulin-regulated membrane aminopeptidase (IRAP). IRAP is a type II integral membrane spanning protein belonging to the M1 family of aminopeptidases and is predominantly found in GLUT4 vesicles in insulin-responsive cells. Three hypotheses for the memory-potentiating effects of the AT(4) receptor/IRAP ligands, Ang IV and LVV-hemorphin 7, are proposed: (i) acting as potent inhibitors of IRAP, they may prolong the action of endogenous promnestic peptides; (ii) they may modulate glucose uptake by modulating trafficking of GLUT4; (iii) IRAP may act as a receptor, transducing the signal initiated by ligand binding to its C-terminal domain to the intracellular domain that interacts with several cytoplasmic proteins.
血管紧张素AT(4)受体最初被定义为六肽血管紧张素IV（Ang IV）的特异性、高亲和力结合位点。随后，肽LVV-血啡肽7也被证明是AT(4)受体的生物活性配体。向正常啮齿动物中枢给予Ang IV、其类似物或LVV-血啡肽7可显著增强学习和记忆，并逆转在失忆动物模型中观察到的记忆缺陷。AT(4)受体分布广泛，存在于一系列组织中，包括肾上腺、肾脏、肺和心脏。在肾脏中，Ang IV可增加肾皮质血流量，并降低离体肾近端小管中的Na(+)转运。AT(4)受体最近被鉴定为跨膜酶，即胰岛素调节的膜氨基肽酶（IRAP）。IRAP是一种II型整合膜跨膜蛋白，属于氨基肽酶M1家族，主要存在于胰岛素反应性细胞的GLUT4囊泡中。提出了关于AT(4)受体/IRAP配体Ang IV和LVV-血啡肽7记忆增强作用的三种假说：（i）作为IRAP的有效抑制剂，它们可能延长内源性记忆增强肽的作用；（ii）它们可能通过调节GLUT4的转运来调节葡萄糖摄取；（iii）IRAP可能作为一种受体，将配体与其C末端结构域结合引发的信号转导至与几种细胞质蛋白相互作用的细胞内结构域。
