Characterization of the desensitization properties of five dopamine receptor subtypes and alternatively spliced variants of dopamine D 2 and D 4 receptors

Abstract

Proper regulation of brain dopaminergic activity is essential for maintaining normal mental functions. In this study, the regulatory properties of five different dopamine receptor subtypes and alternative splicing variants of dopamine D 2 and D 4 were examined. The stimulation of D 1R, D 2R, D 5R but not D 3R, D 4R caused the robust translocation of β-arrestin to the plasma membrane. When D 1R or D 3R were co-expressed with D 2R, D 1R significantly inhibited the sequestration of D 2R, suggesting that the inhibitory effects of D 1R on the D 2R sequestration could explain the synergistic activity between two receptors. The sequestration of alternatively spliced isoforms of D 2R was differently regulated by GRKs and β-arrestins. Three alternative splicing variants of D 4R produced a similar level of β-arrestin translocation, and the studies with the deletion mutants of D 4R within the third cytoplasmic loop revealed that the regions containing the SH3-binding domains are responsible for the β-arrestin translocation.