Novel Regulatory Mechanism of Canonical Wnt Signaling by Dopamine D2 Receptor through Direct Interaction with β-Catenin

Classical G protein-coupled receptors (GPCRs) and canonical Wnt pathways were believed to use distinct signaling pathways. However, recent studies have shown that these two pathways interact each other by sharing several intermediate signaling components. Recent in vivo studies showed that antipsychotic drugs, which block dopamine D2-like receptors, increase the cellular levels of downstream signaling components of canonical Wnt pathways, such as dishevelled (Dvl), glycogen synthase kinase 3 beta (GSK3 beta), and beta-catenin. These results suggest that some functional interactions might exist between Wnt pathway and D2-like receptors. In this study, we show that among five different dopamine receptor subtypes, D-2 receptor (D2R) selectively inhibited the Wnt signaling, which was measured by lymphoid enhancing factor-1 (LEF-1)-dependent transcriptional activities. D2R-mediated inhibition of Wnt signaling was agonist- and G protein-independent and did not require receptor phosphorylation or endocytosis. D2R inhibited the LEF-1-dependent transcriptional activities, and this inhibitory activity was not affected by the inhibition of GSK-3 beta, suggesting that D2R inhibited the Wnt signaling by acting on the downstream of GSK3 beta. D2R directly interacted with beta-catenin through the second and third loops, leading to a reduction of beta-catenin distribution in the nucleus, resulting in an inhibition of LEF-1-dependent transcription. This is a novel mechanism for the regulation of canonical Wnt signaling by GPCRs, in which receptor proteins recruit beta-catenin from cytosol to the plasma membrane, resulting in the decrement of the beta-catenin/LEF-1dependent transcription in the nucleus.