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Vol. 282, Issue 3, 1219-1227, 1997
Department of Pharmacology, University of Nebraska Medical Center,
Omaha, Nebraska
Long-term exposure to agonist down-regulates receptor expression for
many G protein-coupled receptors. This decrease in receptor density
could occur through either an increase in receptor degradation or a
decrease in receptor synthesis. We studied the mechanism of
down-regulation of the alpha-2A and alpha-2B
adrenergic receptor subtypes transfected into the Chinese hamster ovary
cell line as well as the alpha-2A receptor endogenous to the
HT29 cell line. The rate constants for receptor appearance and
disappearance were calculated from the recovery of receptor expression
after irreversible inactivation of the existing receptor population
with an alkylating agent. In the presence of the agonist
norepinephrine, the receptor subtypes in all three cell lines
down-regulated to about 50% with a half-time of 2.5 hr. When
recovering in the presence of norepinephrine after irreversible
inactivation, the rate of receptor degradation increased approximately
2-fold for all three cell lines with little change in the rate of
synthesis. During this recovery, the transfected alpha-2A
receptor exhibited a half-life of 3.0 hr, which agrees with the 2.7-hr
half-time of down-regulation in the presence of norepinephrine. In
contrast, the transfected alpha-2B receptor and the
endogenous alpha-2A receptor had a half-life of 1.2 hr and
8.9 hr, respectively. For only the endogenous alpha-2A
receptor, pertussis toxin increased the half-time of down-regulation to 9.8 hr, similar to the 8.9-hr receptor half-life in the presence of
norepinephrine during recovery after irreversible inactivation. Our
results indicate that the mechanism of down-regulation of the
alpha-2A and -2B adrenergic receptor subtypes is an increase in the rate of receptor degradation.
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