Characterization of the desensitization properties of five dopamine receptor subtypes and alternatively spliced variants of dopamine D2 and D4 receptors

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 D2 and D4 were examined. The stimulation of D1R, D2R, D5R but not D3R, D4R caused the robust translocation of β-arrestin to the plasma membrane. When D1R or D3R were co-expressed with D2R, D1R significantly inhibited the sequestration of D2R, suggesting that the inhibitory effects of D1R on the D2R sequestration could explain the synergistic activity between two receptors. The sequestration of alternatively spliced isoforms of D2R was differently regulated by GRKs and β-arrestins. Three alternative splicing variants of D4R produced a similar level of β-arrestin translocation, and the studies with the deletion mutants of D4R within the third cytoplasmic loop revealed that the regions containing the SH3-binding domains are responsible for the β-arrestin translocation.