beta2-Adrenergic receptor regulation by GIT1, a G protein-coupled receptor kinase-associated ADP ribosylation factor GTPase-activating protein.
Abstract
G protein-coupled receptor activation leads to the membrane recruitment and activation
of G protein-coupled receptor kinases, which phosphorylate receptors and lead to their
inactivation. We have identified a novel G protein-coupled receptor kinase-interacting
protein, GIT1, that is a GTPase-activating protein (GAP) for the ADP ribosylation
factor (ARF) family of small GTP-binding proteins. Overexpression of GIT1 leads to
reduced beta2-adrenergic receptor signaling and increased receptor phosphorylation,
which result from reduced receptor internalization and resensitization. These cellular
effects of GIT1 require its intact ARF GAP activity and do not reflect regulation
of GRK kinase activity. These results suggest an essential role for ARF proteins in
regulating beta2-adrenergic receptor endocytosis. Moreover, they provide a mechanism
for integration of receptor activation and endocytosis through regulation of ARF protein
activation by GRK-mediated recruitment of the GIT1 ARF GAP to the plasma membrane.
Type
Journal articleSubject
ADP-Ribosylation FactorsAdaptor Proteins, Signal Transducing
Amino Acid Sequence
Animals
Binding Sites
Cattle
Cell Cycle Proteins
Cell Line
Cell Membrane
Cyclic AMP-Dependent Protein Kinases
G-Protein-Coupled Receptor Kinase 2
GTP-Binding Proteins
GTPase-Activating Proteins
Gene Expression
Humans
Kinetics
Male
Molecular Sequence Data
Organ Specificity
Phosphoproteins
Proteins
Receptors, Adrenergic, beta-2
Recombinant Proteins
Rod Cell Outer Segment
Spodoptera
Transfection
beta-Adrenergic Receptor Kinases
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https://hdl.handle.net/10161/7826Collections
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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
Richard Thomas Premont
Associate Professor in Medicine
Critical physiological events throughout the body are controlled by extracellular
signals from neurotransmitters and hormones acting on cell surface receptors. Receptors
transduce these signals to alter intracellular metabolism and cellular responsiveness
through heterotrimeric G protein/second messenger pathways or through small GTP-binding
protein/protein kinase cascades. The mechanisms that control the responsiveness of
target organ G protein-coupled receptors include receptor ph
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