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Adrenoceptor Desensitization: Current Understanding of Mechanisms

G蛋白偶联受体 异三聚体G蛋白 脱敏(药物) G蛋白偶联受体激酶 细胞生物学 生物 痛苦 同源性脱敏 信号转导 内化 G蛋白 受体 生物化学 政治 政治学 法学
作者
Dina Maaliki,Aneese A. Jaffa,Suzanne A. Nasser,Amirhossein Sahebkar,Ali H. Eid
出处
期刊:Pharmacological Reviews [American Society for Pharmacology & Experimental Therapeutics]
卷期号:76 (3): 358-387 被引量:3
标识
DOI:10.1124/pharmrev.123.000831
摘要

G-protein coupled receptors (GPCRs) transduce a wide range of extracellular signals. They are key players in the majority of biological 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 pathological 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 down-regulation. 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 biological 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 physiological responsiveness through desensitization and biased agonism. Significance Statement A sophisticated network of proteins orchestrates the molecular regulation of G protein coupled receptor (GPCR) activity. Adrenoceptors are GPCRs that play vast roles in many physiological processes. Without tightly-controlled desensitization of these receptors, homeostatic imbalance may ensue, thus precipitating various diseases. Here, we critically appraise the mechanisms implicated in adrenoceptor desensitization. A better understanding of these mechanisms helps identify new druggable targets within the GPCR desensitization machinery and opens exciting therapeutic fronts in the treatment of several pathologies.
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