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

• Published in: Biochemical and biophysical research communications Vol. 479; no. 2; pp. 398 - 403
• Main Authors: Zhang, Xiaowei, Kim, Kyeong-Man
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 14.10.2016
• Subjects: Dopamine D4 receptor; Endocytosis; Palmitoylation; Signaling; Surface expression; Signaling; Endocytosis; Dopamine D4 receptor; Palmitoylation; Surface expression
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2016.09.094

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 D4-4, 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. [Display omitted] •Palmitoylation of D4R was studied in relation to its role in receptor function.•The D4-4 variant of D4R was palmitoylated at residue C467 of the carboxyl-terminal tail.•Palmitoylation was required for D4R surface expression, endocytosis, and signaling.•Switching the carboxyl-terminal tails of D2R and D4R reversed their palmitoylation-related functions.