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  • Title: Agonist-dependent internalization of the angiotensin II type one receptor (AT1): role of C-terminus phosphorylation in recruitment of beta-arrestins.
    Author: Kule CE, Karoor V, Day JN, Thomas WG, Baker KM, Dinh D, Acker KA, Booz GW.
    Journal: Regul Pept; 2004 Aug 15; 120(1-3):141-8. PubMed ID: 15177932.
    Abstract:
    Beta-arrestins play a role in AT1 endocytosis by binding the cytoplasmic, C-terminus region T332-S338, the major site of angiotensin II (Ang II)-induced phosphorylation. However, the processes responsible for recruiting beta-arrestin to the activated receptor are poorly defined. In this study, we used CHO-K1 and HEK 293 cells expressing wild-type or mutant AT1 to investigate two possibilities: activated AT1 induces global relocation of beta-arrestins to the plasma membrane or the phosphorylated C-terminus acts as bait to attract beta-arrestins. Results obtained using high osmolarity and dominant-negative beta-arrestin confirmed that internalization of AT1 in both CHO-K1 and HEK 293 cells is predominately via clathrin-mediated endocytosis involving beta-arrestin, and substitution of T332, S335, T336 and S338 with alanine to preclude phosphorylation markedly attenuated AT1 internalization. Confocal microscopy revealed that wild-type AT1 induced a time-dependent translocation of GFP-tagged beta-arrestins 1 and 2 to the cell surface. In contrast, the TSTS/A mutant did not traffic beta-arrestin 1 at all, and only trafficked beta-arrestin 2 weakly. Results of rescue-type experiments were consistent with the idea that both beta-arrestins are able to interact with the non-phosphorylated receptor, albeit with much lower affinity and beta-arrestin 1 less so than beta-arrestin 2. In conclusion, this study shows that the high affinity binding of beta-arrestins to the phosphorylated C-terminus is the predominant mechanism of agonist-induced beta-arrestin recruitment to the cell surface and AT1 receptor.
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