TY - JOUR
T1 - Roles of protein kinase C and actin-binding protein 280 in the regulation of intracellular trafficking of dopamine D3 receptor
AU - Cho, Eun Young
AU - Cho, Dong Im
AU - Park, Jae H.
AU - Kurose, Hitoshi
AU - Caron, Marc G.
AU - Kim, Kyeong Man
PY - 2007/9
Y1 - 2007/9
N2 - 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)/β-arrestin-directed internalization. This suggests that there might be an alternative pathway that regulates D 3R 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 D 3R 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.
AB - 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)/β-arrestin-directed internalization. This suggests that there might be an alternative pathway that regulates D 3R 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 D 3R 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.
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U2 - 10.1210/me.2007-0202
DO - 10.1210/me.2007-0202
M3 - Article
C2 - 17536008
AN - SCOPUS:34548339698
VL - 21
SP - 2242
EP - 2254
JO - Molecular Endocrinology
JF - Molecular Endocrinology
SN - 0888-8809
IS - 9
ER -