Phosphorylation by cyclic AMP-dependent protein kinase modulates agonist binding to the D2 dopamine receptor.

Phosphorylation of striatal membranes by cyclic AMP-dependent protein kinase resulted in a reduction in the affinity of the D2 dopamine receptor toward its agonist N-propylnorapomorphine while the affinity to D2-specific antagonists remained unchanted. The inhibitory effects observed by phosphorylation and guanine nucleotides on agonist binding to the D2 receptor were additive. The purified D2 dopamine receptor from bovine striatum was specifically phosphorylated by cyclic AMP-dependent protein kinase with an apparent stoichiometry of 0.7 mol phosphate/mol receptor. The phosphorylated purified D2 receptor also exhibited a reduced agonist binding activity with no change in antagonist binding. The action of cyclic AMP-dependent protein kinase on both the membrane preparation and the purified D2 receptor was inhibited by a specific inhibitor of the kinase. These data indicate that phosphorylation mediated by cyclic AMP-dependent protein kinase may represent a physiological pathway for modulation of the receptor binding activity.