Clathrin-mediated endocytosis is responsible for the lysosomal degradation of dopamine D3 receptor

• Published in: Biochemical and biophysical research communications Vol. 476; no. 4; pp. 245 - 251
• Main Authors: Zhang, Xiaohan, Sun, Ningning, Zheng, Mei, Kim, Kyeong-Man
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.08.2016
• Subjects: antipsychotics; cAMP-dependent protein kinase; Clathrin - metabolism; Degradation; Desensitization; Dopamine D3 receptor; dopamine receptors; Endocytosis; HEK293 Cells; Humans; Internalization; Lysosomes - metabolism; phosphorylation; Protein kinase C; Protein Kinase C beta - metabolism; Proteolysis; Receptors, Dopamine D3 - metabolism; serine; Signal Transduction; Degradation; Protein kinase C; Desensitization; Dopamine D3 receptor; Internalization; Dopamine D receptor
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2016.05.104

GRK2-/β-Arrestin- and PKA-/PKC-mediated desensitization, internalization, and degradation are three representative pathways for regulating G protein-coupled receptors (GPCRs). Compared with GRK2/β-arrestin-mediated ones, functional relationship among the aforementioned three regulatory processes mediated by PKA/PKC is less clear. Dopamine D3 receptor (D3R), a major target of currently available antipsychotic drugs, is a typical GPCR that selectively undergoes PKC-mediated regulation. In the present study, we examined PKC-mediated internalization of D3R in correlation with its roles in desensitization and degradation. Our results showed that the kinase activity of PKCβII and the 229th and 257th serine residues of D3R were required for PKC-mediated desensitization, internalization, and degradation of D3R. PMA treatment ubiquitinated D3R and induced its degradation through lysosomal pathway. Blockade of clathrin-mediated internalization inhibited PKC-mediated lysosomal degradation of D3R but did not affect its desensitization. These results suggested that PKC-mediated phosphorylation of D3R involved clathrin-mediated internalization, which was important for the lysosomal degradation of D3R. [Display omitted] •PKC-mediated internalization of D3R were studied in correlation with its roles in desensitization and degradation.•PKC-mediated internalization of D3R selectively occurred through clathrin-mediated pathway.•PKC-mediated internalization did not affect either the basal signaling or desensitization of D3R.•Receptor phosphorylation was required for the ubiquitination of D3R.•Clathrin-mediated internalization of D3R was responsible for lysosomal degradation.