G-protein coupled receptors (GPCRs) transduce a wide range of extracellular signals. They are key players in the majority of biologic functions including vision, olfaction, chemotaxis, and immunity. However, as essential as most of them are to body function and homeostasis, overactivation of GPCRs has been implicated in many pathologic diseases such as cancer, asthma, and heart failure (HF). Therefore, an important feature of G protein signaling systems is the ability to control GPCR responsiveness, and one key process to control overstimulation involves initiating receptor desensitization. A number of steps are appreciated in the desensitization process, including cell surface receptor phosphorylation, internalization, and downregulation. Rapid or short-term desensitization occurs within minutes and involves receptor phosphorylation via the action of intracellular protein kinases, the binding of β-arrestins, and the consequent uncoupling of GPCRs from their cognate heterotrimeric G proteins. On the other hand, long-term desensitization occurs over hours to days and involves receptor downregulation or a decrease in cell surface receptor protein level. Of the proteins involved in this biologic phenomenon, β-arrestins play a particularly significant role in both short- and long-term desensitization mechanisms. In addition, β-arrestins are involved in the phenomenon of biased agonism, where the biased ligand preferentially activates one of several downstream signaling pathways, leading to altered cellular responses. In this context, this review discusses the different patterns of desensitization of the α₁-, α₂- and the β adrenoceptors and highlights the role of β-arrestins in regulating physiologic responsiveness through desensitization and biased agonism.

中文翻译：

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肾上腺素受体脱敏：目前对机制的理解


G 蛋白偶联受体 (GPCR) 转导多种细胞外信号。它们是大多数生物功能的关键参与者，包括视觉、嗅觉、趋化性和免疫。然而，尽管 GPCR 中的大多数对于身体功能和体内平衡至关重要，但 GPCR 的过度激活与许多病理性疾病有关，例如癌症、哮喘和心力衰竭 (HF)。因此，G蛋白信号系统的一个重要特征是能够控制GPCR反应性，而控制过度刺激的一个关键过程涉及启动受体脱敏。脱敏过程中有许多步骤，包括细胞表面受体磷酸化、内化和下调。快速或短期脱敏在几分钟内发生，涉及通过细胞内蛋白激酶的作用进行受体磷酸化、 β-抑制蛋白的结合以及随后的 GPCR 与其同源异三聚体 G 蛋白的解偶联。另一方面，长期脱敏发生在数小时至数天内，并涉及受体下调或细胞表面受体蛋白水平降低。在参与这种生物现象的蛋白质中， β-抑制蛋白在短期和长期脱敏机制中发挥着特别重要的作用。此外， β-抑制蛋白参与偏向激动现象，其中偏向配体优先激活几个下游信号传导途径之一，导致细胞反应改变。 在此背景下，本综述讨论了α ₁ -、 α ₂ - 和β肾上腺素受体的不同脱敏模式，并强调了β - 抑制素通过脱敏和偏向激动调节生理反应性的作用。