Roles of protein kinase C and actin-binding protein 280 in the regulation of intracellular trafficking of dopamine D3 receptor

Eun Young Cho, Dong Im Cho, Jae H. Park, Hitoshi Kurose, Marc G. Caron, Kyeong Man Kim

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Abstract

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.

Original languageEnglish
Pages (from-to)2242-2254
Number of pages13
JournalMolecular Endocrinology
Volume21
Issue number9
DOIs
Publication statusPublished - Sep 1 2007

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Dopamine D3 Receptors
Microfilament Proteins
Protein Kinase C
Arrestin
Phosphorylation
Filamins
Acetates
G-Protein-Coupled Receptor Kinases
Dynamins
Caveolin 1
Behavior Control
Site-Directed Mutagenesis
Endocytosis
Serine

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Endocrinology

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Roles of protein kinase C and actin-binding protein 280 in the regulation of intracellular trafficking of dopamine D3 receptor. / Cho, Eun Young; Cho, Dong Im; Park, Jae H.; Kurose, Hitoshi; Caron, Marc G.; Kim, Kyeong Man.

In: Molecular Endocrinology, Vol. 21, No. 9, 01.09.2007, p. 2242-2254.

Research output: Contribution to journalArticle

Cho, Eun Young ; Cho, Dong Im ; Park, Jae H. ; Kurose, Hitoshi ; Caron, Marc G. ; Kim, Kyeong Man. / Roles of protein kinase C and actin-binding protein 280 in the regulation of intracellular trafficking of dopamine D3 receptor. In: Molecular Endocrinology. 2007 ; Vol. 21, No. 9. pp. 2242-2254.
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