beta-adrenergic receptor up-regulation induced by nadolol is mediated via signal transduction pathway coupled to alpha-adrenergic receptors.

摘要

Although up-regulation of beta-adrenergic receptors (beta-ARs) occurs after long-term use of their antagonists in various tissues, the available data are little on mechanisms of beta-AR up-regulation induced by their continuous blockade. The present study attempted to clarify mechanisms of beta-AR up-regulation using mouse cerebral cortical neurons continuously exposed to nadolol (10 nM), a non-selective beta-AR antagonist, for 24 h. Nadolol dose-dependently induced both subtypes of beta-ARs, beta- and beta-ARs, which were not suppressed by protein A kinase inhibition with KT5720. On the other hand, blockade of alpha-ARs, which are immunohistochemically confirmed to be co-localized with beta-ARs in the same neurons, significantly inhibited only beta-AR up-regulation and the expression of beta-ARs did not alter. In addition, phenylephrine, an agonist specific to alpha-ARs up-regulated beta-ARs, but not beta-ARs. Under the conditions with beta-AR up-regulation, the level of phosphorylated protein kinase Calpha (pPKCalpha) increased, which is significantly suppressed by prazosin, an alpha1-AR antagonist. Furthermore, nadolol decreased the degradation of mRNA of beta-ARs, but not beta-ARs. These results indicate that the nadolol-induced beta-AR up-regulation is mediated via PKC-relating pathway via alpha-AR activation with stabilizing beta-AR mRNA and that the increased expression of beta-ARs is regulated by pathways different from those for beta-AR expression.