In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 105, No. 29 ( 2008-07-22), p. 9988-9993
Abstract:
β-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 β-arrestin-mediated signaling. The recent discovery of β-arrestin-biased ligands and receptor mutants has allowed characterization of these independent “G protein-mediated” and “β-arrestin-mediated” signaling mechanisms of 7TMRs. However, the molecular mechanisms underlying the dual functions of β-arrestins remain unclear. Here, using an intramolecular BRET (bioluminescence resonance energy transfer)-based biosensor of β-arrestin 2 and a combination of biased ligands and/or biased mutants of three different 7TMRs, we provide evidence that β-arrestin can adopt multiple “active” conformations. Surprisingly, phosphorylation-deficient mutants of the receptors are also capable of directing similar conformational changes in β-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 β-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 β-arrestins, thereby governing their functional specificity.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.0804246105
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2008
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
