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Vol. 61, Issue 4, 806-816, April 2002
Medical Research Service, Veterans Affairs Medical Center;
Departments of Behavioral Neuroscience, Psychiatry, and Physiology
& Pharmacology, Oregon Health and Science University, Portland,
Oregon
The aim of this study was to use pharmacological inhibition of protein
kinase A and mutation of potential protein kinase A phosphorylation
sites to determine the role of protein kinase A-catalyzed
phosphorylation of the dopamine D1 receptor in
agonist-stimulated desensitization and internalization of the receptor.
To facilitate purification and imaging of the D1 receptor,
we attached a polyhistidine tag to the amino terminus and enhanced
green fluorescent protein to the carboxyl terminus of the receptor
(D1-EGFP). D1-EGFP was similar to the untagged
D1 receptor in terms of affinity for agonist and antagonist
ligands, coupling to G proteins, and stimulation of cyclic AMP
accumulation. D1-EGFP and two mutants in which either Thr268 or Ser380 was replaced with Ala were stably expressed in NS20Y
neuroblastoma cells. Pretreatment with the protein kinase A inhibitor
H-89
(N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide) or substitution of Ala for Thr268 reduced agonist-stimulated
phosphorylation of the receptor and resulted in diminished trafficking
of the receptor to the perinuclear region of the cell. Substitution of Ala for Thr268 had no effect, however, on agonist-induced receptor sequestration or desensitization of cyclic AMP accumulation.
Substitution of Ala for Ser380 had no effect on D1 receptor
phosphorylation, sequestration, desensitization, or trafficking to the
perinuclear region. We conclude that protein kinase A-dependent
phosphorylation of the D1 receptor on Thr268 regulates a
late step in the sorting of the receptor to the perinuclear region of
the cell, but that phosphorylation of Thr268 is not required for
receptor sequestration or maximal desensitization of cyclic AMP accumulation.
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