Abstract
Background and Aim We have previously reported that certain bile acids, including chenodeoxycholic acid (CDCA), stimulate glucagon receptor (GR) down-regulation through a heterologous, PKC-dependent mechanism. The aim of this study was to further investigate the homologous versus heterologous GR down-regulation mechanisms. Methhods Rat GR cDNA was fused to GFP and internalization was monitored by fluorescence microscopy, as well as by binding studies using 125I-glucagon in transfected HEK293 cells. Results The glucagon-induced GR internalization is at least partially mediated by β-arrestin 1 and 2 and involves GRK2, GRK3 and GRK5. The effect of GRK overexpression is potentiated by PMA suggesting involvement of PKC in the GR desensitization. We have reported that CDCA and PMA induce GR internalization in the absence of glucagon. However, while glucagon stimulates translocation and activation of PKCα in a time-dependent manner, PKCα is not involved in GR internalization induced by glucagon. Similarly, although the bile acid CDCA stimulates PKCα translocation to the plasma membrane, and PKCα activation/phosphorylation, it does not stimulate homologous GR internalization. Conclusion While glucagon and CDCA activate PKC, PKCα is apparently not directly involved in the internalization of the GR by glucagon. Homologous GR down-regulation involves GRKs, whereas the CDCA-induced and PKC-dependent heterologous GR down-regulation most probably involves GR and Gs uncoupling. Furthermore, PKC could play a role in post-endocytic sorting of internalized GRs.
Published Version
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