D₃ dopamine receptor (D₃R) is expressed mainly in parts of the brain that control the emotional behaviors. It is believed that the improper regulation of D₃R is involved in the etiology of Schizophrenia. Desensitization of D₃R is weakly associated with GRK/-arrestin directed internalization. This suggests that there might be an alternative pathway that regulates D₃R signaling. This report shows that D₃R undergoes robust PKC-dependent sequestration that is accompanied by receptor phosphorylation and the desensitization of signaling. PKC-dependent D₃R sequestration, which was enhanced by PKC- or -, was dynamin-dependent but independent of GRK, -arrestin, or caveolin1. Site-directed mutagenesis of all possible phosphorylation sites within the intracellular loops of D₃R identified serine residues at positions 229 and 257 as the critical amino acids responsible for PMA-induced D₃R phosphorylation, sequestration, and desensitization. In addition, the LxxY endocytosis motif, which is located between residues 252 and 255, was found to play accommodating roles for PMA-induced D₃R sequestration. A continuous interaction with the actin binding protein 280 (filamin A), which was previously known to interact with D₃R, is required for PMA-induced D₃R sequestration. In conclusion, the PKC-dependent but GRK-/-arrestin-independent phosphorylation of D₃R is the main pathway responsible for the sequestration and desensitization of D₃R. Filamin A is essential for both the efficient signaling and sequestration of D₃R.