RGS4 exerts inhibitory activities on the signaling of dopamine D2 receptor and D3 receptor through the N-terminal region

Abstract

Dopamine D2 receptor and D3 receptor (D2R and D3R) are the major targets for current antipsychotic drugs, and their proper regulation has pathological and pharmacological significance. This study was conducted to understand the functional roles and molecular mechanisms of RGS proteins (RGS2, RGS4, and RGS9-2) on the signaling of D2R and D3R. RGS proteins were co-expressed with D2R and D3R in HEK-293 cells. The protein interactions between RGS proteins and D2R/D3R, and effects of RGS proteins on the internalization, signaling, and desensitization of D2R/D3R were determined. In addition, the RGS4 proteins were subdivided into N-terminal region, RGS domain, and the C-terminal region, and the specific subdomain of RGS4 protein involved in the regulation of the signaling of D2R/D3R was determined. All of RGS proteins we tested interacted with D2R/D3R. RGS4 exerted potent inhibitory activities on the signaling of D2R/D3R. RGS9-2 exerted selective but moderate inhibitory activity on D3R and the internalization of D2R. RGS2 had no effect. The N-terminal domain of RGS4 was involved in its interaction with D2R and D3R and was required for the inhibitory activity of the RGS domain. The study for the first time showed that RGS4 is the major RGS protein which interacts through the N-terminal region and exerts potent inhibitory activities on the signaling of D2R and D3R.