Palmitoylation of the carboxyl-terminal tail of dopamine D4 receptor is required for surface expression, endocytosis, and signaling

The amino acid sequences and signaling pathways of D2-like dopamine receptors (D₂R, D₃R, and D₄R) are highly conserved. D₄R 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 D₂R and D₃R reported that palmitoylation is important for the proper functioning of D₃R. Although D₄R 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_4-4, an alternatively spliced form of D₄R, was palmitoylated on Cys467, the terminal amino acid residue of the receptor. When palmitoylation of D₄R was inhibited, by either mutation of the consensus site or by treatment with the palmitoylation inhibitor 2-bromopalmitate (2BP), D₄R cell surface expression, signaling, and endocytosis were all impaired. Exchanging the carboxyl-terminal tails of D₂R and D₄R 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 D₂-like receptors, palmitoylation occurs exclusively in the D₃R and D₄R family members, with the D₄R tail being sufficient to endow D₂R 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 D₄R, which has implications for the treatment of various neurological and psychiatric disorders.

Dopamine D(4) receptor; Endocytosis; Palmitoylation; Signaling; Surface expression.