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The effects of acute and chronic nadolol treatment on β2AR signaling in HEK293 cells

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Abstract

Nadolol (NAD) is a β-adrenergic receptor blocker with inverse agonist activity at βARs. Previous studies in our laboratory showed that chronic treatment with NAD decreased airway resistance response (R aw) to the muscarinic agonist methacholine in a murine model of asthma while acute treatment with NAD increased R aw (Callaerts-Vegh et al., Proc Natl Acad Sci U S A 101:4948–4953, 2004). Chronic treatment with NAD also caused decreased airway inflammation and mucin content in a murine asthma model (Nguyen et al., Am J Respir Cell Mol Biol 38:256–262, 2008). In this study, we examined the effects of nadolol on β2AR levels and signaling components downstream of the β2AR using a line of HEK293 cells expressing human β2ARs. Chronic treatment with NAD increased β2AR protein levels and decreased receptor degradation, consistent with receptor stabilization by the inverse agonist. Basal cAMP levels decreased after 5 min of treatment with NAD but increased after a 24-h treatment. A 5-min treatment with NAD decreased forskolin-stimulated phosphorylation at the β2AR PKA site Ser 262 while a 24-h treatment with NAD increased it. In contrast, chronic treatment with NAD had no effect on phosphorylation of the β2AR GRK site at Ser 355, 356. Chronic treatment with NAD upregulated cellular levels of Gαs but had no effect on Gαi. Chronic NAD treatment therefore increases cellular cAMP levels by mechanisms that include the upregulation of β2AR and Gαs. This effect may explain in part the beneficial effects of chronic nadolol treatment on airway contractility.

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Acknowledgments

This work was supported by the Strategic Program for Asthma Research of the American Asthma Foundation (R.A.B.), and by the American Heart Association (B.J.K).

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The authors declare that they have no conflict of interest.

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Correspondence to Brian J. Knoll.

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Peng, H., Bond, R.A. & Knoll, B.J. The effects of acute and chronic nadolol treatment on β2AR signaling in HEK293 cells. Naunyn-Schmied Arch Pharmacol 383, 209–216 (2011). https://doi.org/10.1007/s00210-010-0591-9

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  • DOI: https://doi.org/10.1007/s00210-010-0591-9

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