GRK2-/beta-Arrestin- and PKA-/PK-mediated desensitization, internalization, and degradation are three representative pathways for regulating G protein-coupled receptors (GPCRs). Compared with GRK2/beta-arrestin-mediated ones, functional relationship among the aforementioned three regulatory processes mediated by PKA/PKC is less clear. Dopamine D-3 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 PKC beta II 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. (C) 2016 Elsevier Inc. All rights reserved.