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Adrenoceptor Desensitization: Current Understanding of Mechanisms.

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

Authors

Dina Maaliki

Aneese A. Jaffa

Amirhossein Sahbekar

Ali H Eid



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.

Citation

Maaliki, D., Jaffa, A. A., Nasser, S., Sahbekar, A., & Eid, A. H. (2024). Adrenoceptor Desensitization: Current Understanding of Mechanisms. Pharmacological Reviews, 76(3), 358-387. https://doi.org/10.1124/pharmrev.123.000831

Journal Article Type Review
Acceptance Date Jan 18, 2024
Online Publication Date May 2, 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 3
Pages 358-387
DOI https://doi.org/10.1124/pharmrev.123.000831
Keywords Receptors, G-Protein-Coupled - metabolism - physiology, beta-Arrestins - metabolism, Humans, Animals, Signal Transduction, Receptors, Adrenergic - metabolism - physiology
Public URL https://keele-repository.worktribe.com/output/794730