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Vol. 59, Issue 2, 310-321, February 2001
Molecular Neuropharmacology Section, Experimental Therapeutics
Branch, National Institute of Neurological Disorders and Stroke,
National Institutes of Health, Bethesda, Maryland
Exposure of D1 dopamine receptors to agonists results in
rapid desensitization of the receptor-stimulated accumulation of cAMP.
It is believed that agonist-induced phosphorylation of the receptor
plays a critical role in the processes that underlie this phenomenon.
To investigate the role of agonist-induced receptor phosphorylation, a
FLAG epitope was added to the amino terminus of the rat D1
dopamine receptor and this construct was stably expressed in C6 glioma
cells. It was found that the D1 receptor was
stoichiometrically phosphorylated under basal conditions and that its
phosphorylation state was increased by 2- to 3-fold upon exposure of
the cells to dopamine for 10 min. The dopamine-induced receptor
phosphorylation could be blocked by D1-selective
antagonists but was unaffected by inhibitors of either protein kinase A
or protein kinase C. The incorporation of phosphate into the receptor was rapid but transient, despite the continued presence of dopamine. A
comparison of the rates of receptor phosphorylation
(t1/2 < 1 min) and dopamine-induced desensitization
(t1/2 ~7 min) revealed that receptor phosphorylation was
not the rate limiting step for receptor desensitization. Upon removal
of dopamine, the receptor was rapidly dephosphorylated
(t1/2 ~10 min) and this was not blocked by agents (i.e.,
concanavalin A or hypertonic sucrose) that inhibit D1
receptor internalization. Using specific inhibitors, the phosphatase involved in D1 receptor dephosphorylation was shown not to
correlate with the recently identified "G protein-coupled receptor
phosphatase" (Proc Natl Acad Sci USA
92:8343-8347, 1995). These results suggest that the
phosphorylated D1 receptor is processed through a
novel recovery pathway and that internalization is not required for
receptor dephosphorylation.
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