期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2008
卷号：105
期号：29
页码：9988-9993
DOI：10.1073/pnas.0804246105
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：{beta}-arrestins critically regulate G protein-coupled receptors (GPCRs), also known as seven-transmembrane receptors (7TMRs), both by inhibiting classical G protein signaling and by initiating distinct {beta}-arrestin-mediated signaling. The recent discovery of {beta}-arrestin-biased ligands and receptor mutants has allowed characterization of these independent "G protein-mediated" and "{beta}-arrestin-mediated" signaling mechanisms of 7TMRs. However, the molecular mechanisms underlying the dual functions of {beta}-arrestins remain unclear. Here, using an intramolecular BRET (bioluminescence resonance energy transfer)-based biosensor of {beta}-arrestin 2 and a combination of biased ligands and/or biased mutants of three different 7TMRs, we provide evidence that {beta}-arrestin can adopt multiple "active" conformations. Surprisingly, phosphorylation-deficient mutants of the receptors are also capable of directing similar conformational changes in {beta}-arrestin as is the wild-type receptor. This indicates that distinct receptor conformations induced and/or stabilized by different ligands can promote distinct and functionally specific conformations in {beta}-arrestin even in the absence of receptor phosphorylation. Our data thus highlight another interesting aspect of 7TMR signaling--i.e., functionally specific receptor conformations can be translated to downstream effectors such as {beta}-arrestins, thereby governing their functional specificity.
