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Expression of beta-adrenergic receptor up-regulation is mediated by two different processes

Seitaro Ohkuma1, Masashi Katsura, Masahiro Shibasaki

  • 1Department of Pharmacology, Kawasaki Medical School, Kurashiki 701-0192, Japan. sohkuma@bcc.kawasaki-m.ac.jp

Brain Research
|August 22, 2006
PubMed

Insights

Sustained exposure to nadolol up-regulates beta-adrenergic receptors (beta-ARs) through two distinct mechanisms. These involve increased receptor protein translocation and, later, enhanced receptor protein and mRNA synthesis.

Area of Science:

  • Neuropharmacology
  • Molecular Biology
  • Cellular Neuroscience

Background:

  • Beta-adrenergic receptors (beta-ARs) play crucial roles in neuronal function.
  • Understanding receptor regulation is vital for developing targeted therapies.
  • Non-selective beta-AR antagonists like nadolol can induce adaptive changes in receptor expression.

Purpose of the Study:

  • To elucidate the mechanisms underlying beta-AR up-regulation induced by sustained nadolol exposure in mouse cerebrocortical neurons.
  • To differentiate between rapid and delayed responses in receptor expression and synthesis.

Main Methods:

  • Primary mouse cerebrocortical neuron cultures were exposed to nadolol (10(-8) M).
  • Quantification of [3H]CGP-12177 binding to measure beta-AR density.
  • Analysis of beta1- and beta2-AR mRNA levels.
  • Inhibition studies using cycloheximide (protein synthesis inhibitor) and Actinomycin D (mRNA synthesis inhibitor).
  • Western blot analysis to assess receptor protein translocation.

Main Results:

  • Nadolol dose- and time-dependently increased beta-AR binding, with a plateau at 12 hours.
  • Beta1- and beta2-AR mRNA levels increased significantly after 24 hours, plateauing at 3 days.
  • Scatchard analysis confirmed increased receptor density, not altered affinity.
  • Cycloheximide did not affect the magnitude of nadolol-induced binding increase, suggesting a component independent of new protein synthesis.
  • Actinomycin D inhibited the up-regulation when administered later, indicating a role for mRNA synthesis in the delayed response.
  • Increased receptor protein translocation from cytosol to membrane occurred within 24 hours.
  • Two distinct processes mediate up-regulation: rapid translocation and delayed synthesis-dependent mechanisms.

Conclusions:

  • Nadolol-induced beta-AR up-regulation involves at least two distinct pathways.
  • A rapid phase involves increased translocation of pre-existing receptor proteins.
  • A delayed phase depends on de novo receptor protein and mRNA synthesis.

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