β1-Adrenergic receptor up-regulation induced by nadolol is mediated via signal transduction pathway coupled to α1-adrenergic receptors

Although up-regulation of β-adrenergic receptors (β-ARs) occurs after long-term use of their antagonists in various tissues, the available data are little on mechanisms of β-AR up-regulation induced by their continuous blockade. The present study attempted to clarify mechanisms of β-AR up-regulation using mouse cerebral cortical neurons continuously exposed to nadolol (10 nM), a non-selective β-AR antagonist, for 24 h. Nadolol dose-dependently induced both subtypes of β-ARs, β1- and β2-ARs, which were not suppressed by protein A kinase inhibition with KT5720. On the other hand, blockade of α1-ARs, which are immunohistochemically confirmed to be co-localized with β-ARs in the same neurons, significantly inhibited only β1-AR up-regulation and the expression of β2-ARs did not alter. In addition, phenylephrine, an agonist specific to α1-ARs up-regulated β1-ARs, but not β2-ARs. Under the conditions with β-AR up-regulation, the level of phosphorylated protein kinase Cα (pPKCα) increased, which is significantly suppressed by prazosin, an α1-AR antagonist. Furthermore, nadolol decreased the degradation of mRNA of β1-ARs, but not β2-ARs. These results indicate that the nadolol-induced β1-AR up-regulation is mediated via PKC-relating pathway via α1-AR activation with stabilizing β1-AR mRNA and that the increased expression of β2-ARs is regulated by pathways different from those for β1-AR expression.

► β-AR antagonist, nadolol, upregulated expression of both β1- and β2-AR.
► Only upregulation of β1-AR is inhibited by α1-AR antagonist prazosin.
► Inhibition of PKC prevented the nadolol-induced β1-AR upregulation.
► α1-AR agonist phenylephrine increased just β1-AR expression.