Duke University Medical Center, Durham, NC 27710, USA.
Mol Pharmacol. 2010 Dec;78(6):983-92. doi: 10.1124/mol.110.067066. Epub 2010 Sep 20.
β-Adrenergic and angiotensin II type 1A receptors are therapeutic targets for the treatment of a number of common human diseases. Pharmacological agents designed as antagonists for these receptors have positively affected the morbidity and mortality of patients with hypertension, heart failure, and renal disease. Antagonism of these receptors, however, may only partially explain the therapeutic benefits of β-blockers and angiotensin receptor blockers given the emerging concept of functional selectivity or biased agonism. This new pharmacological paradigm suggests that multiple signaling pathways can be differentially modified by a single ligand-receptor interaction. This review examines the functional selectivity of β-adrenergic and angiotensin II type 1A receptors with respect to their ability to signal via both G protein-dependent and G protein-independent mechanisms, with a focus on the multifunctional protein β-arrestin. Also highlighted are the concept of "biased signaling" through β-arrestin mediated pathways, the affect of ligand/receptor modification on such biased agonism, and the implications of functional selectivity for the development of the next generation of β-blockers and angiotensin receptor blockers.
β-肾上腺素能和血管紧张素 II 型 1A 受体是治疗许多常见人类疾病的治疗靶点。设计为这些受体拮抗剂的药物已对高血压、心力衰竭和肾病患者的发病率和死亡率产生了积极影响。然而，这些受体的拮抗作用可能仅部分解释β受体阻滞剂和血管紧张素受体阻滞剂的治疗益处，因为新兴的功能性选择性或偏向激动作用概念。这种新的药理学范式表明，单个配体-受体相互作用可以使多种信号通路得到不同程度的修饰。这篇综述考察了β-肾上腺素能和血管紧张素 II 型 1A 受体的功能性选择性，以及它们通过 G 蛋白依赖和非依赖机制进行信号转导的能力，重点是多功能蛋白β-arrestin。还强调了通过β-arrestin 介导途径的“偏向信号传递”的概念，配体/受体修饰对这种偏向激动作用的影响，以及功能性选择性对下一代β受体阻滞剂和血管紧张素受体阻滞剂的发展的意义。
