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Vol. 57, Issue 3, 539-545, March 2000
Molecular Pharmacology Group, Division of Biochemistry and
Molecular Biology, Institute of Biomedical and Life Sciences,
University of Glasgow, Glasgow, Scotland, United Kingdom (T.M.P.); and
Departments of Medicine and Pharmacology, Duke University Medical
Center, Durham, North Carolina (G.L.S.)
Activation of the A3 adenosine receptor (A3AR)
contributes to the cardioprotective, bronchoconstrictive, and
hypotensive effects of adenosine. Agonist occupation of the
A3AR results in a rapid desensitization of receptor
function, which is associated with the phosphorylation of the receptor
protein by one or more members of the G protein-coupled receptor kinase
family of protein kinases. Although we demonstrated previously that
phosphorylation of the C-terminal 14 amino acids of the rat
A3AR is crucial for rapid desensitization to occur, the
identity of the critical phosphorylation sites has remained unknown.
Here, we demonstrate that the simultaneous mutation of
Thr307, Thr318, and Thr319 to Ala
residues dramatically reduces agonist-stimulated phosphorylation and
rapid desensitization of the rat A3AR. Individual mutation of each residue demonstrated that Thr318 and
Thr319 are the major sites of phosphorylation.
Phosphorylation at Thr318 appeared to be necessary to
observe phosphorylation at Thr319, but not vice versa.
However, the replacement of Thr318 with a glutamate residue
demonstrated that the simple addition of negative charge at position
318 was not sufficient to rescue phosphorylation at position 319. In
addition, the mutation of two predicted palmitoylation-site cysteine
residues proximal to the regulatory domain resulted in the appearance
of an agonist-independent basal phosphorylation. Therefore, G
protein-coupled receptor kinase-mediated phosphorylation of the
C-terminal tail of the A3AR in situ appears to follow a
sequential mechanism, perhaps involving receptor depalmitoylation, with
phosphorylation at Thr318 being particularly important.
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