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Vol. 56, Issue 4, 675-683, October 1999

Regulation of D1 Dopamine Receptors with Mutations of Protein Kinase Phosphorylation Sites: Attenuation of the Rate of Agonist-Induced Desensitization

Dong Jiang and David R. Sibley

Molecular Neuropharmacology Section, Experimental Therapeutics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland

Investigations of D1 receptor regulation have suggested a role for cAMP-dependent protein kinase (PKA) in agonist-induced desensitization and down-regulation of receptor expression. Given the presence of at least four possible consensus recognition sites for PKA on the D1 receptor protein, a reasonable hypothesis is that some of these PKA-mediated effects are caused by phosphorylation of the receptor. As an initial test of this hypothesis, we used site-directed mutagenesis to create a mutant D1 receptor with substitutions at each of its four potential PKA phosphorylation sites. The modified amino acids are as follows: Thr135 to Val, Ser229 to Ala, Thr268 to Val, and Ser380 to Ala. Characterization of the wild-type and mutant receptors stably expressed in C6 glioma cells suggests that the mutations have no effect on receptor expression, antagonist or agonist affinities, or on functional coupling with respect to cAMP generation. Similarly, dopamine preincubation of the stably transfected C6 cells expressing either the wild-type or mutated D1 receptors results in an agonist-induced loss of ligand binding activity (down-regulation) in an identical fashion. In contrast, the time of onset of dopamine-induced desensitization is greatly attenuated in the quadruple mutant receptor. After 1 h of dopamine pretreatment, the wild-type receptor exhibits ~80% desensitization of the cAMP response, whereas the mutant receptor is desensitized by only ~20%. Further analyses of single mutated receptors, in which only one of the four putative phosphorylation sites is modified, reveals that Thr268 in the third cytoplasmic loop of the receptor protein is primarily responsible for regulating the desensitization kinetics. These results are consistent with the hypothesis that phosphorylation of the D1 receptor on Thr268 is important for rapid agonist-induced homologous desensitization.

Copyright © 1999 by U.S. Government


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