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Halothane facilitates the translocation of GRK-2 and phosphorylation of ß2- adrenergic receptor in rat synaptosomes

Shigeru Saito, MD PhD^*, Yuji Kadoi, MD PhD^*, Akihiro Ohyama, MD^*, and Fumio Goto, MD PhD^*

^* From the Departments of Anesthesiology and Reanimatology, and
Molecular and Cellular Neurobiology, Gunma University School of Medicine, Japan.

Address correspondence to: Dr. Shigeru Saito, Department of Anesthesiology and Reanimatology, Gunma University School of Medicine, 3-39-22, Showa-machi, Maebashi, 371-8511, Japan. Phone: +81-27-220-8454; Fax: +81-27-220-8473; E-mail: shigerus{at}news.sb.gunma-u.ac.jp

Purpose: To examine the effect of halothane on ß2-adrenergic receptor phosphorylation and on G-protein coupled receptor kinase (GRK), responsible for ß2-receptor downregulation.

Methods: Rat forebrain synaptosomes were incubated for 30 min with halothane 1 or 2%. The cytosolic and membrane fractions were separated, and phosphorylation activity of recombinant ß2-adrenergic receptor was quantified autoradiographically using ³²P labeled adenosine triphosphate. Phosphorylation activity of a specific GRK-2 substrate, was examined by measuring ³²P binding. Subcellular localization of the enzyme was immunologically analyzed by Western blotting.

Results: Halothane 2% decreased the phosphorylation activity of the recombinant receptor in the cytosol fraction, regardless of 10 µM isoproterenol (ISP) (P < 0.01), which activity in the membrane fraction was increased (P < 0.01). Phosphorylation activity of the synthetic peptide decreased in the cytosol obtained from synaptosomes exposed to halothane 2% (P < 0.05). In contrast, activity in the membrane increased by exposure to halothane 2% (P < 0.01). The concentration of GRK-2 decreased in the cytosol obtained from synaptosomes exposed to halothane 1% or 2% (decreases of 8.3 ± 1.2% @ 1%, and 18.0 ± 2.1% @ 2%, P < 0.05). In the membrane, exposure to halothane 1% or 2% increased the GRK-2 amount dose dependently (22.5 ± 3.1% @ 1% , and by 45.7 ± 6.1% @ 2%, P < 0.01).

Conclusion: Halothane could facilitate translocation of GRK-2 and possibly promote the downregulation of ß2-adrenergic receptors in the synaptic membrane. The anesthetic action and hemodynamic suppressive action of halothane may be related to this phenomenon.

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