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Decreased Glucagon Responsiveness by Bile Acids: A Role for Protein Kinase C and Glucagon Receptor Phosphorylation

Gastroenterology Research Laboratory, Department of Biochemistry and Molecular Biology (T.I., L.K., J.M., B.P., K.C., B.B.) and Department of Medicine (B.B.), The George Washington University, Washington, D.C. 20037

Address all correspondence and requests for reprints to: Bernard Bouscarel, Ph.D., D.Sc., Gastroenterology Research Laboratory, The George Washington University Medical Center, 2300 I Street, Northwest, 523 Ross Hall, Washington, D.C. 20037. E-mail: bbouscarel{at}mfa.gwu.edu.

Dihydroxy bile acids like chenodeoxycholic acid (CDCA) induce heterologous glucagon receptor desensitization. We previously demonstrated that protein kinase C (PKC) was activated by certain bile acids and mediated the CDCA-induced decrease in glucagon responsiveness. The aim of the present study was to explore the role of PKC in the phosphorylation and desensitization of the glucagon receptor by CDCA. Desensitization was evaluated by measuring adenylyl cyclase activity. Receptor phosphorylation was assayed by metabolic labeling with [-³²P] ATP. Protein kinase C (PKC) translocation and activation was visualized by fluorescence microscopy. CDCA decreased cAMP production induced by glucagon in a dose-dependent manner without affecting cAMP synthesis through stimulation of either stimulatory GTP-binding protein (Gs) by NaF or adenylyl cyclase by forskolin. The CDCA-induced inhibition of adenylyl cyclase activity was potentiated by the phosphatase inhibitor, okadaic acid. The desensitizing effect of CDCA was bile acid-specific and was significantly reduced in the presence of PKC inhibitors and after PKC down-regulation by phorbol 12-myristate 13-acetate. CDCA increased glucagon receptor phosphorylation more than 3-fold at concentrations as low as 25 µM. Furthermore, CDCA significantly stimulated human recombinant PKC autophosphorylation in vitro, as well as PKC translocation to the plasma membrane and phosphorylation in vivo at concentrations as low as 25 µM. CDCA also stimulated PKC translocation to the perinuclear region. Activated PKC, PKC, and to a lesser extent, PKC, phosphorylated the glucagon receptor in vitro. This study demonstrates that certain bile acids, such as CDCA, stimulate phosphorylation and heterologous desensitization of the glucagon receptor, involving at least PKC activation.

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