Phosphorylation by Cyclic AMP‐Dependent Protein Kinase Modulates Agonist Binding to the D₂ Dopamine Receptor

Abstract

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.

Novel Role of Brain Stem Pedunculopontine Tegmental Adenylyl Cyclase in the Regulation of Spontaneous REM Sleep in the Freely Moving Rat

“…Thus, based on the results of these earlier studies and the present study, it is reasonable to suggest that the intracellular cAMP signal transduction pathway in the brainstem is critically involved in the regulation of REM sleep. Since the activation of the cAMP signal transduction pathway causes protein phosphorylation by activating protein kinase A (PKA) that ultimately causes activation of ion channels, receptor up/down regulation, neurotransmitter synthesis/release, and gene expression (Gilman, 1987;Elazar and Fuchs, 1991;Ginty et al, 1991;Wang et al, 1991Wang et al, , 1993, it is logical to speculate that part of this cAMP activation-mediated REM sleep generating mechanism in the cholinergic cell compartment of the PPT involves activation of the cAMP-dependent PKA signal transduction pathway. However, we acknowledge that future experimental work will be necessary to confirm or refute this pathway's involvement.…”

6-Hydroxydopamine lesions of rat substantia nigra up-regulate dopamine-induced phosphorylation of the cAMP-response element-binding protein in striatal neurons.

“…Altered activity of these molecules may influence "upstream" targets, such as ion channels (30,32,(51)(52)(53)(54)(55)(56)(57) and neurotransmitter receptors (20,47), as well as "downstream" targets. Altered activities of the molecules that regulate CREB phosphorylation after destruction of the SNC may directly alter striatal responses to subsequent exposures to dopamine as well as gene expression.…”