Journal
EXPERIMENTAL CELL RESEARCH
Volume 317, Issue 20, Pages 2981-2994Publisher
ELSEVIER INC
DOI: 10.1016/j.yexcr.2011.10.001
Keywords
Glucagon receptor; PKC alpha; GRK; beta-Arrestin
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Funding
- National Institutes of Health [DK56108]
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Glucagon levels are elevated in diabetes and some liver diseases. Increased glucagon secretion leads to abnormal stimulation of glucagon receptors (GRs) and consequent elevated glucose production in the liver. Blocking glucagon receptor signaling has been proposed as a potential treatment option for diabetes and other conditions associated with hyperglycemia. Elucidating mechanisms of GR desensitization and downregulation may help identify new drug targets besides GR itself. The present study explores the mechanisms of GR internalization and the role of PKC alpha. GPCR kinases (GRKs) and beta-arrestins therein. We have reported previously that PKCa mediates GR phosphorylation and desensitization. While the PKC agonist, PMA, did not affect GR internalization when tested alone, it increased glucagon-mediated GR internalization by 25-40% in GR-expressing HEK-293 cells (HEK-GR cells). In both primary hepatocytes and HEK-GR cells, glucagon treatment recruited PKCa to the plasma membrane where it colocalized with GR. We also observed that overexpression of GRK2, GRK3, or GRK5 enhanced GR internalization. In addition, we found that GR utilizes both clathrin- and caveolin-mediated endocytosis in HEK-GR cells. Glucagon triggered translocation of both beta-arrestin1 and beta-arrestin2 from the cytosol to the perimembrane region, and overexpression of beta-arrestin1 and beta-arrestin2 increased GR internalization. Furthermore, both beta-arrestin1 and beta-arrestin2 colocalized with GR and with Cav-1, suggesting the possible involvement of these arrestins in GR internalization. (C) 2011 Elsevier Inc. All rights reserved.
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