Impaired formation of beta-adrenergic receptor-nucleotide regulatory protein complexes in pseudohypoparathyroidism.
Abstract
Decreased activity of the guanine nucleotide regulatory protein (N) of the adenylate
cyclase system is present in cell membranes of some patients with pseudohypoparathyrodism
(PHP-Ia) whereas others have normal activity of N (PHP-Ib). Low N activity in PHP-Ia
results in a decrease in hormone (H)-stimulatable adenylate cyclase in various tissues,
which might be due to decreased ability to form an agonist-specific high affinity
complex composed of H, receptor (R), and N. To test this hypothesis, we compared beta-adrenergic
agonist-specific binding properties in erythrocyte membranes from five patients with
PHP-Ia (N = 45% of control), five patients with PHP-Ib (N = 97%), and five control
subjects. Competition curves that were generated by increasing concentrations of the
beta-agonist isoproterenol competing with [125I]pindolol were shallow (slope factors
less than 1) and were computer fit to a two-state model with corresponding high and
low affinity for the agonist. The agonist competition curves from the PHP-Ia patients
were shifted significantly (P less than 0.02) to the right as a result of a significant
(P less than 0.01) decrease in the percent of beta-adrenergic receptors in the high
affinity state from 64 +/- 22% in PHP-Ib and 56 +/- 5% in controls to 10 +/- 8% in
PHP-Ia. The agonist competition curves were computer fit to a "ternary complex" model
for the two-step reaction: H + R + N in equilibrium HR + N in equilibrium HRN. The
modeling was consistent with a 60% decrease in the functional concentration of N,
and was in good agreement with the biochemically determined decrease in erythrocyte
N protein activity. These in vitro findings in erythrocytes taken together with the
recent observations that in vivo isoproterenol-stimulated adenylate cyclase activity
is decreased in patients with PHP (Carlson, H. E., and A. S. Brickman, 1983, J. Clin.
Endocrinol. Metab. 56:1323-1326) are consistent with the notion that N is a bifunctional
protein interacting with both R and the adenylate cyclase. It may be that in patients
with PHP-Ia a single molecular and genetic defect accounts for both decreased HRN
formation and decreased adenylate cyclase activity, whereas in PHP-Ib the biochemical
lesion(s) appear not to affect HRN complex formation.
Type
Journal articleSubject
Adenylyl CyclasesAdolescent
Adult
Binding Sites
Child
Erythrocyte Membrane
Female
Humans
Iodine
Male
Middle Aged
Pindolol
Pseudohypoparathyroidism
Receptors, Adrenergic, beta
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https://hdl.handle.net/10161/7881Published Version (Please cite this version)
10.1172/JCI111336Publication Info
Heinsimer, JA; Davies, AO; Downs, RW; Levine, MA; Spiegel, AM; Drezner, MK; ... Lefkowitz,
RJ (1984). Impaired formation of beta-adrenergic receptor-nucleotide regulatory protein complexes
in pseudohypoparathyroidism. J Clin Invest, 73(5). pp. 1335-1343. 10.1172/JCI111336. Retrieved from https://hdl.handle.net/10161/7881.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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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
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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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