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 β(2)AR levels and signaling components downstream of the β(2)AR using a line of HEK293 cells expressing human β(2)ARs. Chronic treatment with
NAD increased β(2)AR
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 β(2)AR 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 β(2)AR GRK site at Ser 355, 356. Chronic treatment with
NAD upregulated cellular levels of G(α)s but had no effect on G(α)i. Chronic
NAD treatment therefore increases cellular cAMP levels by mechanisms that include the upregulation of β(2)AR and G(α)s. This effect may explain in part the beneficial effects of chronic
nadolol treatment on airway contractility.