Inhibition of beta-adrenergic receptor kinase prevents rapid homologous desensitization of beta 2-adrenergic receptors.
Abstract
Homologous (agonist-specific) desensitization of beta-adrenergic receptors (beta ARs)
is accompanied by and appears to require phosphorylation of the receptors. We have
recently described a novel protein kinase, beta AR kinase, which phosphorylates beta
ARs in vitro in an agonist-dependent manner. This kinase is inhibited by two classes
of compounds, polyanions and synthetic peptides derived from the beta 2-adrenergic
receptor (beta 2AR). In this report we describe the effects of these inhibitors on
the process of homologous desensitization induced by the beta-adrenergic agonist isoproterenol.
Permeabilization of human epidermoid carcinoma A431 cells with digitonin was used
to permit access of the charged inhibitors to the cytosol; this procedure did not
interfere with the pattern of isoproterenol-induced homologous desensitization of
beta 2AR-stimulated adenylyl cyclase. Inhibitors of beta AR kinase markedly inhibited
homologous desensitization of beta 2ARs in the permeabilized cells. Inhibition of
desensitization by heparin, the most potent of the polyanion inhibitors of beta AR
kinase, occurred over the same concentration range (5-50 nM) as inhibition of purified
beta AR kinase assessed in a reconstituted system. Inhibition of desensitization by
heparin was accompanied by a marked reduction of receptor phosphorylation in the permeabilized
cells. Whereas inhibitors of beta AR kinase inhibited homologous desensitization,
inhibitors of protein kinase C and of cyclic-nucleotide-dependent protein kinases
were ineffective. These data establish that phosphorylation of beta ARs by beta AR
kinase is an essential step in homologous desensitization of the receptors. They further
suggest a potential therapeutic value of inhibitors of beta AR kinase in inhibiting
agonist-induced desensitization.
Type
Journal articleSubject
AnimalsCell Membrane Permeability
Cricetinae
Digitonin
Drug Tolerance
Heparin
Humans
Isoproterenol
Kinetics
Lung
Phosphorylation
Protein Kinase Inhibitors
Receptors, Adrenergic, beta
Tumor Cells, Cultured
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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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