Akazawa Hiroshi, Yasuda Noritaka, Miura Shin-ichiro, Komuro Issei
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Yamadaoka, Suita, Osaka, Japan.
Methods Enzymol. 2010;485:25-35. doi: 10.1016/B978-0-12-381296-4.00002-6.
The angiotensin II (AngII) type 1 (AT₁) receptor is a seven-transmembrane G-protein-coupled receptor that plays a regulatory role in the physiological and pathological processes of the cardiovascular system. AT₁ receptor inherently shows constitutive activity even in the absence of AngII, and it is activated not only by AngII but also by AngII-independent mechanisms. Especially, mechanical stress induces cardiac hypertrophy through activation of AT₁ receptor without the involvement of AngII. These AngII-independent activities of AT₁ receptor can be inhibited by inverse agonists, but not by neutral antagonists. In this chapter, we describe the methods used for biochemical assessment of inverse agonism of a ligand for AT₁ receptor. Their applications will improve our understanding of receptor activation and inactivation at a molecular level, and contribute to the development of AT₁ receptor blockers possessing superior therapeutic efficacy in cardiovascular diseases.
血管紧张素 II（AngII）1 型（AT₁）受体是一种七跨膜 G 蛋白偶联受体，在心血管系统的生理和病理过程中发挥调节作用。即使在没有 AngII 的情况下，AT₁ 受体本身也表现出组成性活性，并且它不仅被 AngII 激活，还通过不依赖 AngII 的机制被激活。特别是，机械应力通过激活 AT₁ 受体诱导心脏肥大，而不涉及 AngII。AT₁ 受体的这些不依赖 AngII 的活性可被反向激动剂抑制，但不能被中性拮抗剂抑制。在本章中，我们描述了用于对 AT₁ 受体配体的反向激动作用进行生化评估的方法。它们的应用将提高我们在分子水平上对受体激活和失活的理解，并有助于开发在心血管疾病中具有卓越治疗效果的 AT₁ 受体阻滞剂。
