科研之友
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摘要
beta 2-adrenergic receptor (beta 2AR), a member of the GPCR (G-protein coupled receptor) family, is internalized in a ligand-and beta-arrestin-dependent manner into early endosomes, and subsequently recycled back to the plasma membrane. Here, we report that beta-arrestin promotes the activation of the small G protein Arf6, which regulates the recycling and degradation of beta 2AR. We demonstrate in vitro that the C-terminal region of beta-arrestin1 interacts directly and simultaneously with Arf6GDP and its specific exchange factor EFA6, to promote Arf6 activation. Similarly, the ligand-mediated activation of beta 2AR leads to the formation of Arf6GTP in vivo in a beta-arrestin-dependent manner. Expression of either EFA6 or an activated Arf6 mutant caused accumulation of beta 2AR in the degradation pathway. This phenotype could be rescued by the expression of an activated mutant of Rab4, suggesting that Arf6 acts upstream of Rab4. We propose a model in which Arf6 plays an essential role in beta 2AR desensitization. The ligand-mediated stimulation of beta 2AR relocates beta-arrestin to the plasma membrane, and triggers the activation of Arf6 by EFA6. The activation of Arf6 leads to accumulation of beta 2AR in the degradation pathway, and negatively controls Rab4-dependent fast recycling to prevent the re-sensitization of beta 2AR.
- 出版日期2012-9-1
