Role of adenylyl cyclase type 5 in the regulation of the dopamine D3 receptor phosphorylation

Abstract

Adenylyl cyclase type 5 (AC5) is expressed in the brain where the highest density of the dopamine D3 receptor (D3R) has been found. The D3R-mediated Gi/o protein activation leads to a specific inhibition of AC5. Therefore, as AC5 is the main signalosome partner of D3R, I hypothesize that D3R phosphorylation is differentially regulated in cells expressing AC5. In HEK293 cells expressing D3R alone, D3R undergo dopamine-induced phosphorylation. Interestingly, in cells co-expressing AC5 and D3R, D3R undergoes a Galphai-dependent dephosphorylation upon dopamine exposure while retaining its ability to be phosphorylated in a Src-dependent manner under basal conditions. In cells co-expressing D3R and AC5, dopamine-induced D3R dephosphorylation and Gi/o mediated inhibition of cAMP production are specifically blocked by pharmacological inhibitors of the serine/threonine phosphatase PP2B and tyrosine phosphatases. Overall, our results suggest a novel paradigm in G protein-coupled receptor signaling whereby AC5 serves as a potential scaffolding complex containing phosphatases regulating the D3R phosphorylation status.