title: β₁-adrenergic receptor up-regulation induced by nadolol is mediated via signal transduction pathway coupled to α₁-adrenergic receptors.
abstract: 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.
authors.affiliation: Department of Pharmacology, Kawasaki Medical School, Matsushima 577, Kurashiki 701-0192, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Mizuno
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kurokawa
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shibasaki
authors.forename: Seitaro
authors.initials: S
authors.lastname: Ohkuma
mesh_terms: D018663:Adrenergic Agents / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D053119:Benzophenanthridines / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004299:Dopamine beta-Hydroxylase / Q000378:metabolism; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D009248:Nadolol / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D011758:Pyrroles / Q000494:pharmacology; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics / Q000378:metabolism*; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D018663:Adrenergic Agents; D000319:Adrenergic beta-Antagonists; D053119:Benzophenanthridines; D002227:Carbazoles; D004791:Enzyme Inhibitors; D011758:Pyrroles; D018340:Receptors, Adrenergic, alpha-1; D018342:Receptors, Adrenergic, beta-1; D009248:Nadolol; C057416:KT 5720; C016299:chelerythrine; D004299:Dopamine beta-Hydroxylase