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-Arrestin/Green Fluorescent Protein Biosensor for Detecting
G Protein-coupled Receptor Activation
(Received for publication, August 21, 1997)
From the Howard Hughes Medical Institute Laboratories and
Department of Cell Biology, Duke University Medical Center,
Durham, North Carolina 27710
G protein-coupled receptors (GPCR) represent the
single most important drug targets for medical therapy, and information
from genome sequencing and genomic data bases has substantially
accelerated their discovery. The lack of a systematic approach either
to identify the function of a new GPCR or to associate it with a
cognate ligand has added to the growing number of orphan receptors. In
this work we provide a novel approach to this problem using a
-arrestin2/green fluorescent protein conjugate (arr2-GFP). It
provides a real-time and single cell based assay to monitor GPCR
activation and GPCR-G protein-coupled receptor kinase or GPCR-arrestin
interactions. Confocal microscopy demonstrates the translocation of
arr2-GFP to more than 15 different ligand-activated GPCRs. These
data clearly support the common hypothesis that the -arrestin
binding of an activated receptor is a convergent step of GPCR
signaling, increase by 5-fold the number of GPCRs known to interact
with -arrestins, demonstrate that the cytosol is the predominant
reservoir of biologically active -arrestins, and provide the first
direct demonstration of the critical importance of G protein-coupled
receptor kinase phosphorylation to the biological regulation of
-arrestin activity and GPCR signal transduction in living cells. The
use of arr2-GFP as a biosensor to recognize the activation of
pharmacologically distinct GPCRs should accelerate the identification
of orphan receptors and permit the optical study of their signal
transduction biology intractable to ordinary biochemical methods.
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