C-terminal di-leucine motif of dopamine D₁ receptor plays an important role in its plasma membrane trafficking.

The dopamine D₁ receptor (D₁R), a G protein-coupled receptor, plays a critical role in regulating blood pressure through its actions on renal hemodynamics and epithelial ion transport, which are highly linked to its intracellular trafficking. In this study, we generated a series of C-terminal mutants of D₁R that were tagged with or without enhanced yellow fluorescent protein, and analyzed the consequences of these mutants on the plasma membrane trafficking of D₁R and cyclic AMP response to D₁R stimulation. D₁R with mutations within the endocytic recycling signal (amino acid residues 360-382) continued to be functional, albeit decreased relative to wild-type D₁R. Mutation of the palmitoylation site (347C>S) of D₁R did not impair its trafficking to the plasma membrane, but abolished its ability to increase cyclic AMP accumulation. In contrast, replacement of di-leucines (344-345L>A) by alanines resulted in the retention of D₁R in the early endosome, decreased its glycosylation, and prevented its targeting to the plasma membrane. Our studies suggest that di-L motif at the C-terminus of D₁R is critical for the glycosylation and cell surface targeting of D₁R.