Regions of the alpha 1-adrenergic receptor involved in coupling to phosphatidylinositol hydrolysis and enhanced sensitivity of biological function.
Abstract
Regions of the hamster alpha 1-adrenergic receptor (alpha 1 AR) that are important
in GTP-binding protein (G protein)-mediated activation of phospholipase C were determined
by studying the biological functions of mutant receptors constructed by recombinant
DNA techniques. A chimeric receptor consisting of the beta 2-adrenergic receptor (beta
2AR) into which the putative third cytoplasmic loop of the alpha 1AR had been placed
activated phosphatidylinositol metabolism as effectively as the native alpha 1AR,
as did a truncated alpha 1AR lacking the last 47 residues in its cytoplasmic tail.
Substitutions of beta 2AR amino acid sequence in the intermediate portions of the
third cytoplasmic loop of the alpha 1AR or at the N-terminal portion of the cytoplasmic
tail caused marked decreases in receptor coupling to phospholipase C. Conservative
substitutions of two residues in the C terminus of the third cytoplasmic loop (Ala293----Leu,
Lys290----His) increased the potency of agonists for stimulating phosphatidylinositol
metabolism by up to 2 orders of magnitude. These data indicate (i) that the regions
of the alpha 1AR that determine coupling to phosphatidylinositol metabolism are similar
to those previously shown to be involved in coupling of beta 2AR to adenylate cyclase
stimulation and (ii) that point mutations of a G-protein-coupled receptor can cause
remarkable increases in sensitivity of biological response.
Type
Journal articleSubject
Amino Acid SequenceAnimals
Cell Line
Cricetinae
Hydrolysis
Inositol
Inositol Phosphates
Kinetics
Ligands
Molecular Sequence Data
Norepinephrine
Phosphatidylinositols
Plasmids
Protein Conformation
Receptors, Adrenergic, alpha
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https://hdl.handle.net/10161/7864Collections
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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
James B. Duke 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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