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J. Biol. Chem., Vol. 276, Issue 22, 19452-19460, June 1, 2001
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From the Howard Hughes Medical Institute Laboratories, Departments
of Cell Biology and Medicine, Duke University Medical Center,
Durham, North Carolina 27710
Molecular Determinants Underlying the Formation of
Stable Intracellular G Protein-coupled Receptor-
-Arrestin Complexes
after Receptor Endocytosis*
,
-Arrestins bind agonist-activated G
protein-coupled receptors (GPCRs) and mediate their desensitization and
internalization. Although -arrestins dissociate from some receptors
at the plasma membrane, such as the 2 adrenergic receptor, they
remain associated with other GPCRs and internalize with them into
endocytic vesicles. Formation of stable receptor--arrestin complexes
that persist inside the cell impedes receptor resensitization, and the
aberrant formation of these complexes may play a role in GPCR-based
diseases (Barak, L. S., Oakley, R. H., Laporte, S. A.,
and Caron, M. G. (2001) Proc. Natl. Acad. Sci.
U. S. A. 98, 93-98). Here, we investigate the molecular
determinants responsible for sustained receptor/-arrestin interactions. We show in real time and in live human embryonic kidney
(HEK-293) cells that a -arrestin-2-green fluorescent protein conjugate internalizes into endocytic vesicles with agonist-activated neurotensin-1 receptor, oxytocin receptor, angiotensin II type 1A
receptor, and substance P receptor. Using receptor mutagenesis, we
demonstrate that the ability of -arrestin to remain associated with
these receptors is mediated by specific clusters of serine and
threonine residues located in the receptor carboxyl-terminal tail.
These clusters are remarkably conserved in their position within the
carboxyl-terminal domain and serve as primary sites of
agonist-dependent receptor phosphorylation. In addition, we identify a -arrestin mutant with enhanced affinity for the
agonist-activated 2-adrenergic receptor that traffics into endocytic
vesicles with receptors that lack serine/threonine clusters and
normally dissociate from wild-type -arrestin at the plasma membrane.
By identifying receptor and -arrestin residues critical for the
formation of stable receptor--arrestin complexes, these studies
provide novel targets for regulating GPCR responsiveness and treating
diseases resulting from abnormal GPCR/-arrestin interactions.
Recipient of a fellowship award from the Canadian Institutes of
Health Research.
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