Adrenoceptor Desensitization: Current understanding of mechanisms

Maaliki, Dina; Jaffa, Aneese A.; Nasser, Suzanne; Sahbekar, Amirhossein; Eid, Ali H.

Abstract

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.

• Journal Article Type: Review
• Acceptance Date: Jan 30, 2024
• Online Publication Date: Jan 30, 2024
• Publication Date: Mar 1, 2024
• Deposit Date: Apr 16, 2024
• Journal: Pharmacological Reviews
• Print ISSN: 0031-6997
• Electronic ISSN: 1521-0081
• Publisher: American Society for Pharmacology and Experimental Therapeutics
• Peer Reviewed: Peer Reviewed
• Volume: 76
• Issue: 2
• DOI: https://doi.org/10.1124/pharmrev.123.000831
• Keywords: Pharmacology; Molecular Medicine