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

Rosethorne EM, Bradley ME, Kent TC, Charlton SJ - Pharmacol Res Perspect (2015)

Bottom Line: However, a potential consequence of long-term treatment may be the loss of functional response (tachyphylaxis) over time.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus

β2 adrenoceptor-mediated cAMP accumulation in hBSMc. Concentration effect curves for cAMP generation were determined in hBSMc following exposure to β2 adrenoceptor agonists for 2 h. For each individual experiment, data have been normalized to the maximum amount of cAMP produced after addition of 10 μmol/L isoprenaline, and are expressed as means ± SEM for three independent experiments.
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fig01: β2 adrenoceptor-mediated cAMP accumulation in hBSMc. Concentration effect curves for cAMP generation were determined in hBSMc following exposure to β2 adrenoceptor agonists for 2 h. For each individual experiment, data have been normalized to the maximum amount of cAMP produced after addition of 10 μmol/L isoprenaline, and are expressed as means ± SEM for three independent experiments.

Mentions: By monitoring β2 adrenoceptor agonist-induced cAMP signaling in the hBSMc, we demonstrated that the agonists tested showed a range of potencies and intrinsic efficacies in these cells (Fig. 1, Table 1).


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

Rosethorne EM, Bradley ME, Kent TC, Charlton SJ - Pharmacol Res Perspect (2015)

β2 adrenoceptor-mediated cAMP accumulation in hBSMc. Concentration effect curves for cAMP generation were determined in hBSMc following exposure to β2 adrenoceptor agonists for 2 h. For each individual experiment, data have been normalized to the maximum amount of cAMP produced after addition of 10 μmol/L isoprenaline, and are expressed as means ± SEM for three independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4317232&req=5

fig01: β2 adrenoceptor-mediated cAMP accumulation in hBSMc. Concentration effect curves for cAMP generation were determined in hBSMc following exposure to β2 adrenoceptor agonists for 2 h. For each individual experiment, data have been normalized to the maximum amount of cAMP produced after addition of 10 μmol/L isoprenaline, and are expressed as means ± SEM for three independent experiments.
Mentions: By monitoring β2 adrenoceptor agonist-induced cAMP signaling in the hBSMc, we demonstrated that the agonists tested showed a range of potencies and intrinsic efficacies in these cells (Fig. 1, Table 1).

Bottom Line: However, a potential consequence of long-term treatment may be the loss of functional response (tachyphylaxis) over time.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus