D(4) dopamine receptor
plasma membrane
Palmitoylation of the carboxyl-terminal tail of dopamine D<sub>4</sub> receptor is required for surface expression, endocytosis, and signaling.
The amino acid sequences and signaling pathways of D2-like dopamine receptors (D<sub>2</sub>R, D<sub>3</sub>R, and D<sub>4</sub>R) are highly conserved. D<sub>4</sub>R has been suggested to be associated with novelty seeking, and binds with high affinity to an atypical antipsychotic drug with fewer motor function-related side effects than typical neuroleptics. A study comparing D<sub>2</sub>R and D<sub>3</sub>R reported that palmitoylation is important for the proper functioning of D<sub>3</sub>R. Although D<sub>4</sub>R is a member of the D2-like receptor family, its palmitoylation status and the functional significance of any such posttranslational modification are unknown. In this study, it was found that D<sub>4-4</sub>, an alternatively spliced form of D<sub>4</sub>R, was palmitoylated on Cys467, the terminal amino acid residue of the receptor. When palmitoylation of D<sub>4</sub>R was inhibited, by either mutation of the consensus site or by treatment with the palmitoylation inhibitor 2-bromopalmitate (2BP), D<sub>4</sub>R cell surface expression, signaling, and endocytosis were all impaired. Exchanging the carboxyl-terminal tails of D<sub>2</sub>R and D<sub>4</sub>R resulted in a switching of the palmitoylation phenotype, as well as concomitant changes in functionality, such as receptor surface expression, endocytosis, and signaling. Despite the high degree of homology in the carboxyl-terminal tails of D<sub>2</sub>-like receptors, palmitoylation occurs exclusively in the D<sub>3</sub>R and D<sub>4</sub>R family members, with the D<sub>4</sub>R tail being sufficient to endow D<sub>2</sub>R with palmitoylation-associated functionality. Thus, this study provides new insights into a consensus sequence for palmitoylation, as well as possible strategies for the regulation of D<sub>4</sub>R, which has implications for the treatment of various neurological and psychiatric disorders.