title: Functional desensitization of the β 2 adrenoceptor is not dependent on agonist efficacy.
abstract: Chronic treatment with β 2 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, β 2 adrenoceptor internalization and β-arrestin-2 recruitment were monitored using β 2·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.
authors.affiliation: Novartis Institutes for Biomedical Research Wimblehurst Road, Horsham, West Sussex, RH12 5AB, United Kingdom ; School of Life Sciences, Queen's Medical Centre, University of Nottingham Nottingham, NG7 2UH, United Kingdom.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Rosethorne
authors.affiliation: Novartis Institutes for Biomedical Research Wimblehurst Road, Horsham, West Sussex, RH12 5AB, United Kingdom.
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Bradley
authors.affiliation: Novartis Institutes for Biomedical Research Wimblehurst Road, Horsham, West Sussex, RH12 5AB, United Kingdom.
authors.forename: Toby C
authors.initials: TC
authors.lastname: Kent
authors.affiliation: Novartis Institutes for Biomedical Research Wimblehurst Road, Horsham, West Sussex, RH12 5AB, United Kingdom ; School of Life Sciences, Queen's Medical Centre, University of Nottingham Nottingham, NG7 2UH, United Kingdom.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Charlton
keywords: COPD; agonist efficacy; functional desensitization; β2 adrenoceptor