Functional desensitization of the ? 2 adrenoceptor is not dependent on agonist efficacy

Rosethorne, Elizabeth M.; Bradley, Michelle E.; Kent, Toby C.; Charlton, Steven J.

Abstract

© 2015 John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics. Chronic treatment with β2 adrenoceptor agonists is recommended as a first-line maintenance therapy for chronic obstructive pulmonary disease (COPD). However, a potential consequence of long-term treatment may be the loss of functional response (tachyphylaxis) over time. In this study, we have investigated the tendency of such agonists, with a range of efficacies, to develop functional desensitization to cAMP responses in primary human bronchial smooth muscle cells following prolonged agonist exposure. The data show that upon repeat exposure, all agonists produced functional desensitization to the same degree and rate. In addition, β2 adrenoceptor internalization and β-arrestin-2 recruitment were monitored using β2·eGFP visualization and the PathHunter™ β-arrestin-2 assay, respectively. All agonists were capable of causing robust receptor internalization and β-arrestin-2 recruitment, the rate of which was influenced by agonist efficacy, as measured in those assays. In summary, although a relationship exists between agonist efficacy and the rate of both receptor internalization and β-arrestin-2 recruitment, there is no correlation between agonist efficacy and the rate or extent of functional desensitization.

• Journal Article Type: Article
• Acceptance Date: Sep 11, 2014
• Online Publication Date: Jan 5, 2015
• Publication Date: 2015-02
• Deposit Date: Mar 16, 2018
• Publicly Available Date: Jan 27, 2020
• Journal: Pharmacology Research and Perspectives
• Print ISSN: 2052-1707
• Electronic ISSN: 2052-1707
• Publisher: Wiley Open Access
• Peer Reviewed: Peer Reviewed
• Volume: 3
• Issue: 1
• Article Number: e00101
• DOI: https://doi.org/10.1002/prp2.101
• Public URL: https://nottingham-repository.worktribe.com/output/1118623
• Publisher URL: https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1002/prp2.101
• PMID: 25692019