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Decreased glucagon responsiveness by bile acids: a role for protein kinase Calpha and glucagon receptor

Tadashi Ikegami1, Lada Krilov, Jianping Meng

  • 1Gastroenterology Research Laboratory, The George Washington University Medical Center, 2300 I Street, Northwest, 523 Ross Hall, Washington, D.C. 20037, USA.

Endocrinology
|August 19, 2006
PubMed

Insights

Chenodeoxycholic acid (CDCA), a dihydroxy bile acid, triggers glucagon receptor desensitization by activating protein kinase C (PKC). This leads to increased glucagon receptor phosphorylation and reduced glucagon responsiveness.

Area of Science:

  • Endocrinology
  • Cell Biology
  • Biochemistry

Background:

  • Dihydroxy bile acids, such as chenodeoxycholic acid (CDCA), are known to induce heterologous glucagon receptor desensitization.
  • Protein kinase C (PKC) has been implicated in mediating the CDCA-induced decrease in glucagon responsiveness.

Purpose of the Study:

  • To investigate the specific role of PKC in the phosphorylation and subsequent desensitization of the glucagon receptor induced by CDCA.
  • To elucidate the molecular mechanisms by which CDCA affects glucagon receptor signaling.

Main Methods:

  • Adenylyl cyclase activity assays were used to evaluate receptor desensitization.
  • Metabolic labeling with [gamma-(32)P] ATP assessed receptor phosphorylation.
  • Fluorescence microscopy visualized PKC translocation and activation.
  • In vitro kinase assays examined the direct phosphorylation of the glucagon receptor by activated PKC isoforms.

Main Results:

  • CDCA dose-dependently decreased glucagon-induced cAMP production without affecting adenylyl cyclase activity directly.
  • CDCA significantly increased glucagon receptor phosphorylation and stimulated PKCalpha and PKCdelta translocation and activation.
  • Activated PKC isoforms (PKCalpha, PKCzeta, PKCdelta) were shown to directly phosphorylate the glucagon receptor in vitro.

Conclusions:

  • Chenodeoxycholic acid (CDCA) induces glucagon receptor desensitization through a mechanism involving PKC activation.
  • PKC-mediated phosphorylation of the glucagon receptor is a key step in the desensitization process.
  • This study highlights the role of bile acids in regulating hormone receptor function via kinase signaling pathways.

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