title: Palmitoylation of the carboxyl-terminal tail of dopamine D4receptor is required for surface expression, endocytosis, and signaling.
abstract: 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.
authors.affiliation: Department of Pharmacology, College of Pharmacy, Chonnam National University, Gwangju, 61186, Republic of Korea.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, College of Pharmacy, Chonnam National University, Gwangju, 61186, Republic of Korea. Electronic address: kmkim@jnu.ac.kr.
authors.forename: Kyeong-Man
authors.initials: KM
authors.lastname: Kim
mesh_terms: D014150:Antipsychotic Agents / Q000737:chemistry; D019921:Biotinylation; D002462:Cell Membrane / Q000378:metabolism*; D003545:Cysteine / Q000737:chemistry; D004705:Endocytosis; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D054878:Lipoylation; D010169:Palmitic Acids / Q000737:chemistry*; D010957:Plasmids / Q000378:metabolism; D000072417:Protein Domains; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000378:metabolism; D050638:Receptors, Dopamine D4 / Q000737:chemistry* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D014150:Antipsychotic Agents; C581293:DRD2 protein, human; C493593:DRD3 protein, human; C493599:DRD4 protein, human; D010169:Palmitic Acids; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D050638:Receptors, Dopamine D4; D003545:Cysteine
keywords: Dopamine D(4) receptor; Endocytosis; Palmitoylation; Signaling; Surface expression