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

Author:

Cho Eun-Young1,Cho Dong-Im1,Park Jae H.2,Kurose Hitoshi3,Caron Marc G.4,Kim Kyeong-Man1

Affiliation:

1. Department of Pharmacology (E.-Y.C., D.-I.C., K.-M.K), College of Pharmacy, Chonnam National University, Kwang-Ju 500-757, Korea;

2. Department of Biochemistry and Cellular and Molecular Biology (J.H.P), University of Tennessee, Knoxville, Tennessee 37996;

3. Department of Pharmacology and Toxicology (H.K.), Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan;

4. Department of Cell Biology (M.G.C.), Duke University Medical Center, Durham, North Carolina 27710

Abstract

AbstractD3 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)/β-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-β or -δ, was dynamin dependent but independent of GRK, β-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-/β-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.

Publisher

The Endocrine Society

Subject

Endocrinology,Molecular Biology,General Medicine

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