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Vol. 57, Issue 3, 546-552, March 2000
Molecular Pharmacology Group, Division of Biochemistry and
Molecular Biology, Institute of Biomedical and Life Sciences,
University of Glasgow, Glasgow, Scotland, United Kingdom
Despite coupling to the same class of inhibitory G proteins and binding
the same physiological ligand, the human A1 and rat A3 adenosine receptors (ARs) desensitize at different rates
in response to sustained agonist exposure. This is due to the ability of the A3AR, but not the A1AR, to serve as a
substrate for rapid phosphorylation and desensitization by members of
the G protein-coupled receptor kinase (GRK) family. The aim of this
study was to investigate whether these differences were also manifested
in their abilities to undergo agonist-dependent receptor
internalization. For the first time, we report that A3ARs
internalize profoundly in response to short-term exposure to agonist
but not activators of second messenger-regulated kinases. The
A3AR-selective antagonist MRS1523 blocked both
A3AR phosphorylation and internalization. Moreover, in
contrast to the A1AR, which internalized quite slowly
(t1/2 = 90 min), A3ARs
internalized rapidly (t1/2 = 10 min) over
a time frame that followed the onset of receptor phosphorylation. A
nonphosphorylated A3AR mutant failed to internalize
over a 60-min time course, suggesting that receptor phosphorylation was
essential for rapid A3AR internalization to occur. In
addition, fusion onto the A1AR of the A3AR
C-terminal domain containing the sites for phosphorylation by GRKs
conferred rapid agonist-induced internalization kinetics
(t1/2 = 10 min) on the resulting chimeric
AR. In conclusion, these data suggest that GRK-stimulated
phosphorylation of threonine residues within the C-terminal domain of
the A3AR is obligatory to observe rapid agonist-mediated internalization of the receptor.
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