Expression of beta-adrenergic receptor up-regulation is mediated by two different processes.
Mechanisms of up-regulation of beta-adrenergic receptors (beta-ARs) induced by sustained exposure to 10(-8) M nadolol, a non-selective beta-AR antagonist, were examined using mouse cerebrocortical neurons. Nadolol dose- and time-dependently increased [3H]CGP-12177 bindings to the particulate fractions. This increase occurred 6 h and attained its plateau 12 h after the exposure, whereas beta1- and beta2-AR mRNA significantly increased 24 h and attained their plateaus 3 days after the exposure. Scatchard analysis revealed that the increased bindings were due to increase of receptor density. The [3H]CGP-12177 bindings to beta1- and beta2-ARs increased both 12 h and 5 days after the exposure. Although cycloheximide (CHX) decreased the bindings with or without nadolol, the extent of increase of the bindings induced by nadolol was not affected by CHX. Actinomycin D (AD) with nadolol showed no affects on the bindings 12 h after nadolol exposure, while AD treated 6 h after nadolol exposure significantly reduced the bindings 48 h after nadolol exposure. During 24 h after nadolol exposure, the increase in proteins of beta1- and beta2-ARs in the neuronal membrane was due to the increased receptor protein translocation from cytosol to membrane. These results indicate that the up-regulation of beta-ARs induced by nadolol is mediated by, at least, two different processes, one is increase in translocation of receptor proteins from cytosol to membrane with no changes in synthesis of receptor proteins and their mRNA and another is dependent on receptor protein synthesis with increased synthesis of their mRNA.
Ohkuma
Seitaro
S
Department of Pharmacology, Kawasaki Medical School, Kurashiki 701-0192, Japan. sohkuma@bcc.kawasaki-m.ac.jp
Katsura
Masashi
M
Shibasaki
Masahiro
M
Tsujimura
Atsushi
A
Hirouchi
Masaaki
M
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000526:Alprenolol / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003513:Cycloheximide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D051379:Mice; D009248:Nadolol / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D011412:Propanolamines / Q000493:pharmacokinetics; D011485:Protein Binding / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013997:Time Factors; D014316:Tritium / Q000493:pharmacokinetics; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; D014316:Tritium; D009248:Nadolol; D000526:Alprenolol; D003513:Cycloheximide; C033394:CGP 12177