De Bundel Dimitri, Smolders Ilse, Vanderheyden Patrick, Michotte Yvette
Research Group Experimental Pharmacology, Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Vrije Universiteit Brussel, Brussels, Belgium.
CNS Neurosci Ther. 2008 Winter;14(4):315-39. doi: 10.1111/j.1755-5949.2008.00057.x.
The central angiotensin system plays a crucial role in cardiovascular regulation. More recently, angiotensin peptides have been implicated in stress, anxiety, depression, cognition, and epilepsy. Angiotensin II (Ang II) exerts its actions through AT(1) and AT(2) receptors, while most actions of its metabolite Ang IV were believed to be independent of AT(1) or AT(2) receptor activation. A specific binding site with high affinity for Ang IV was discovered and denominated "AT(4) receptor". The beneficiary effects of AT(4) ligands in animal models for cognitive impairment and epileptic seizures initiated the search for their mechanism of action. This proved to be a challenging task, and after 20 years of research, the nature of the "AT(4) receptor" remains controversial. Insulin-regulated aminopeptidase (IRAP) was first identified as the high-affinity binding site for AT(4) ligands. Recently, the hepatocyte growth factor receptor c-MET was also proposed as a receptor for AT(4) ligands. The present review focuses on the effects of Ang II and Ang IV on synaptic transmission and plasticity, learning, memory, and epileptic seizure activity. Possible interactions of Ang IV with the classical AT(1) and AT(2) receptor subtypes are evaluated, and other potential mechanisms by which AT(4) ligands may exert their effects are discussed. Identification of these mechanisms may provide a valuable target in the development in novel drugs for the treatment of cognitive disorders and epilepsy.
中枢血管紧张素系统在心血管调节中起着关键作用。最近，血管紧张素肽与应激、焦虑、抑郁、认知和癫痫有关。血管紧张素II（Ang II）通过AT(1)和AT(2)受体发挥作用，而其代谢产物Ang IV的大多数作用被认为与AT(1)或AT(2)受体激活无关。发现了一个对Ang IV具有高亲和力的特异性结合位点，并将其命名为“AT(4)受体”。AT(4)配体在认知障碍和癫痫发作动物模型中的有益作用引发了对其作用机制的探索。事实证明这是一项具有挑战性的任务，经过20年的研究，“AT(4)受体”的性质仍然存在争议。胰岛素调节的氨肽酶（IRAP）最初被确定为AT(4)配体的高亲和力结合位点。最近，肝细胞生长因子受体c-MET也被认为是AT(4)配体的受体。本综述重点关注Ang II和Ang IV对突触传递和可塑性、学习、记忆及癫痫发作活动的影响。评估了Ang IV与经典AT(1)和AT(2)受体亚型可能的相互作用，并讨论了AT(4)配体发挥作用的其他潜在机制。确定这些机制可能为开发治疗认知障碍和癫痫的新药提供有价值的靶点。
