Functional desensitization of the isolated beta-adrenergic receptor by the beta-adrenergic receptor kinase: potential role of an analog of the retinal protein arrestin (48-kDa protein).
Abstract
The beta-adrenergic receptor kinase is an enzyme, possibly analogous to rhodopsin
kinase, that multiply phosphorylates the beta-adrenergic receptor only when it is
occupied by stimulatory agonists. Since this kinase may play an important role in
mediating the process of homologous, or agonist-specific, desensitization, we investigated
the functional consequences of receptor phosphorylation by the kinase and possible
analogies with the mechanism of action of rhodopsin kinase. Pure hamster lung beta
2-adrenergic receptor, reconstituted in phospholipid vesicles, was assessed for its
ability to mediate agonist-promoted stimulation of the GTPase activity of coreconstituted
stimulatory guanine nucleotide-binding regulatory protein. When the receptor was phosphorylated
by partially (approximately 350-fold) purified preparations of beta-adrenergic receptor
kinase, as much as 80% inactivation of its functional activity was observed. However,
the use of more highly purified enzyme preparations led to a dramatic decrease in
the ability of phosphorylation to inactivate the receptor such that pure enzyme preparations
(approximately 20,000-fold purified) caused only minimal (approximately 1off/- 7%)
inactivation. Addition of pure retinal arrestin (48-kDa protein or S antigen), which
is involved in enhancing the inactivating effect of rhodopsin phosphorylation by rhodopsin
kinase, led to partial restoration of the functional effect of beta-adrenergic receptor
kinase-promoted phosphorylation (41 +/- 3% inactivation). These results suggest the
possibility that a protein analogous to retinal arrestin may exist in other tissues
and function in concert with beta-adrenergic receptor kinase to regulate the activity
of adenylate cyclase-coupled receptors.
Type
Journal articleSubject
AnimalsAntigens
Arrestin
Cyclic AMP-Dependent Protein Kinases
Eye Proteins
GTP-Binding Proteins
Humans
In Vitro Techniques
Phosphoproteins
Phosphorylation
Protein Kinases
Receptors, Adrenergic, beta
Retina
beta-Adrenergic Receptor Kinases
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Show full item recordScholars@Duke
Marc G. Caron
James B. Duke Distinguished Professor of Cell Biology
Studies of the mechanisms of action and regulation of hormones and neurotransmitters
at the cellular and molecular levels constitute the main goals our of research activities.
G protein-coupled receptors (GPCR) mediate the actions of signaling molecules from
unicellular organisms to man. We have used adrenergic and dopamine receptors to characterize
the structure/function and regulation mechanisms of these prototypes of G protein-coupled
receptors. Another approach has been to characterize
This author no longer has a Scholars@Duke profile, so the information shown here reflects
their Duke status at the time this item was deposited.
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 Chancellor’s Distinguished Professor of Medicine and
Professor of Biochemistry and Chemistry at the Duke University Medical Center. He
has bee
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