beta-Arrestin 1 and 2 differentially regulate heptahelical receptor signaling and trafficking.
Abstract
The two widely coexpressed isoforms of beta-arrestin (termed beta arrestin 1 and 2)
are highly similar in amino acid sequence. The beta-arrestins bind phosphorylated
heptahelical receptors to desensitize and target them to clathrin-coated pits for
endocytosis. To better define differences in the roles of beta-arrestin 1 and 2, we
prepared mouse embryonic fibroblasts from knockout mice that lack one of the beta-arrestins
(beta arr1-KO and beta arr2-KO) or both (beta arr1/2-KO), as well as their wild-type
(WT) littermate controls. These cells were analyzed for their ability to support desensitization
and sequestration of the beta(2)-adrenergic receptor (beta(2)-AR) and the angiotensin
II type 1A receptor (AT(1A)-R). Both beta arr1-KO and beta arr2-KO cells showed similar
impairment in agonist-stimulated beta(2)-AR and AT(1A)-R desensitization, when compared
with their WT control cells, and the beta arr1/2-KO cells were even further impaired.
Sequestration of the beta(2)-AR in the beta arr2-KO cells was compromised significantly
(87% reduction), whereas in the beta arr1-KO cells it was not. Agonist-stimulated
internalization of the AT(1A)-R was only slightly reduced in the beta arr1-KO but
was unaffected in the beta arr2-KO cells. In the beta arr1/2-KO cells, the sequestration
of both receptors was dramatically reduced. Comparison of the ability of the two beta-arrestins
to sequester the beta(2)-AR revealed beta-arrestin 2 to be 100-fold more potent than
beta-arrestin 1. Down-regulation of the beta(2)-AR was also prevented in the beta
arr1/2-KO cells, whereas no change was observed in the single knockout cells. These
findings suggest that sequestration of various heptahelical receptors is regulated
differently by the two beta-arrestins, whereas both isoforms are capable of supporting
receptor desensitization and down-regulation.
Type
Journal articleSubject
AnimalsArrestins
Cell Line
Cyclic AMP
Humans
Mice
Mice, Knockout
Phosphatidylinositols
Protein Isoforms
Receptor, Angiotensin, Type 1
Receptors, Adrenergic, beta-2
Receptors, Angiotensin
Signal Transduction
beta-Arrestin 1
beta-Arrestin 2
beta-Arrestins
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https://hdl.handle.net/10161/7808Published Version (Please cite this version)
10.1073/pnas.041608198Publication Info
Kohout, TA; Lin, FS; Perry, SJ; Conner, DA; & Lefkowitz, RJ (2001). beta-Arrestin 1 and 2 differentially regulate heptahelical receptor signaling and
trafficking. Proc Natl Acad Sci U S A, 98(4). pp. 1601-1606. 10.1073/pnas.041608198. Retrieved from https://hdl.handle.net/10161/7808.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Robert J. Lefkowitz
The Chancellor's Distinguished Professor of Medicine
Dr. Lefkowitz’s memoir, A Funny Thing Happened on the Way to Stockholm, recounts his
early career as a cardiologist and his transition to biochemistry, which led to his
Nobel Prize win.
Robert J. Lefkowitz, M.D. is James B. Duke Professor of Medicine and Professor of
Biochemistry and Chemistry at the Duke University Medical Center. He has been an Investigator
of the

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