Ligand-induced internalization and recycling of the human neuropeptide Y2 receptor is regulated by its carboxyl-terminal tail.
Ligand-induced internalization and recycling of the human neuropeptide Y2 receptor is regulated by its carboxyl-terminal tail.
复制标题
配体诱导的人神经肽 Y2 受体的内化和再循环受其羧基末端尾部的调节。
DOI：
10.1074/jbc.m110.162156
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发表时间：
2010
期刊：
影响因子：
--
通讯作者：
Beck-Sickinger,AnnetteG
中科院分区：
文献类型：
--
作者：
Walther,Cornelia;Nagel,Stefanie;Gimenez,LuisE;Mörl,Karin;Gurevich,VsevolodV;Beck-Sickinger,AnnetteG
Agonist-induced internalization of G protein-coupled receptors plays an important role in signal regulation. The underlying mechanisms of the internalization of the human neuropeptide Y2receptor (hY2R), as well as its desensitization, endocytosis, and resensitization are mainly unknown. In the present study we have investigated the role of carboxyl-terminal (C-terminal) Ser/Thr residues and acidic amino acids in regulating receptor internalization, arrestin interaction, and recycling by fluorescence microscopy, cell surface enzyme-linked immunosorbent assay, and bioluminescence resonance energy transfer in several cell lines. Strikingly, C-terminal truncation mutants revealed two different internalization motifs. Whereas a distal motif373DSXTEXT379was found to be the primary regulatory internalization sequence acting in concert with arrestin-3, the proximal motif347DXXXSEXSXT356promoted ligand-induced internalization in an arrestin-3-independent manner. Moreover, we identified a regulatory sequence located between these internalization motifs (357FKAKKNLEVRKN368), which serves as an inhibitory element. We found that hY2R recycling is also governed by structural determinants within the proximal internalization motif. In conclusion, these results indicate that the hY2R C terminus is involved in multiple molecular events that regulate internalization, interaction with arrestin-3, and receptor resensitization. Our findings provide novel insights into complex mechanisms of controlled internalization of hY2R, which is likely applicable to other GPCRs.
