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Roles of Protein Kinase C and Actin-Binding Protein 280 in the Regulation of Intracellular Trafficking of Dopamine D₃ Receptor

Department of Pharmacology (E.-Y.C., D.-I.C., K.-M.K), College of Pharmacy, Chonnam National University, Kwang-Ju 500-757, Korea; Department of Biochemistry and Cellular and Molecular Biology (J.H.P), University of Tennessee, Knoxville, Tennessee 37996; Department of Pharmacology and Toxicology (H.K.), Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan; and Department of Cell Biology (M.G.C.), Duke University Medical Center, Durham, North Carolina 27710

Address all correspondence and requests for reprints to: Dr. Kyeong-Man Kim, Department of Pharmacology, College of Pharmacy, Chonnam National University, Kwang-Ju 500-757, Korea. E-mail: kmkim{at}chonnam.ac.kr.

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 G protein-coupled receptor kinase (GRK)/ß-arrestin-directed internalization. This suggests that there might be an alternative pathway that regulates D₃R signaling. This report shows that D₃R undergoes robust protein kinase C (PKC)-dependent sequestration that is accompanied by receptor phosphorylation and the desensitization of signaling. PKC-dependent D₃R sequestration, which was enhanced by PKC-ß or -, was dynamin dependent but independent of GRK, ß-arrestin, or caveolin 1. 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 phorbol-12-myristate-13-acetate (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-/ß-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.

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