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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Caron, M. G. Kim, K. M. Zhang, X. Min, C. Zheng, M. |
| Description | Author Affiliation: Min C ( Department of Pharmacology, College of Pharmacy, Drug Development Research Institute, Chonnam National University, Gwang-Ju, 500-757, Korea.) |
| Abstract | BACKGROUND AND PURPOSE: In addition to typical GPCR kinase (GRK)-/ß-arrestin-dependent internalization, dopamine D3 receptor employed an additional GRK-independent sequestration pathway. In this study, we investigated the molecular mechanism of this novel sequestration pathway. EXPERIMENTAL APPROACH: Radioligand binding, flow cytometry and cell surface biotinylation assay were used to characterize trafficking properties of D2 and D3 receptors. Serine/threonine and N-linked glycosylation mutants of the D3 receptor were utilized to locate receptor regions involved in pharmacological sequestration and desensitization. Various point mutants of the D2 and D3 receptors, whose sequestration and desensitization properties were altered, were combined with knockdown cells of GRKs or ß-arrestins to functionally correlate pharmacological sequestration and desensitization. KEY RESULTS: The D3 receptor, but not the D2 receptor, showed characteristic trafficking behaviour in which receptors were shifted towards the more hydrophobic domains within the plasma membrane without translocation into other intracellular compartments. Among various amino acid residues tested, S145/S146, C147 and N12/19 were involved in pharmacological sequestration and receptor desensitization. Both pharmacological sequestration and desensitization of D3 receptor required ß-arrestins, and functional relationship was observed between two processes when it was tested for D3 receptor variants and agonists. CONCLUSIONS AND IMPLICATIONS: Pharmacological sequestration of D3 receptor accompanies movement of cell surface receptors into a more hydrophobic fraction within the plasma membrane and renders D3 receptor inaccessible to hydrophilic ligands. Pharmacological sequestration is correlated with desensitization of the D3 receptor in a Gßγ- and ß-arrestin-dependent manner. This study provides new insights into molecular mechanism governing GPCR trafficking and desensitization. |
| ISSN | 00071188 |
| e-ISSN | 14765381 |
| Journal | British Journal of Pharmacology |
| Issue Number | 5 |
| Volume Number | 170 |
| Language | English |
| Publisher | Wiley Online Library(on behalf of The British Pharmacological Society) |
| Publisher Date | 2013-11-01 |
| Publisher Place | Great Britain (UK) |
| Access Restriction | Open |
| Subject Keyword | Arrestins Metabolism Dopamine Agonists Pharmacology Endocytosis Drug Effects Receptors, Dopamine D3 Agonists Amino Acid Sequence Genetics Biotinylation Dopamine Dose-Response Relationship, Drug Drug Tolerance Flow Cytometry G-Protein-Coupled Receptor Kinases GTP-Binding Protein Beta Subunits GTP-Binding Protein Gamma Subunits Glycosylation HEK293 Cells Molecular Sequence Data Phosphorylation Point Mutation Protein Conformation Protein Transport Quinpirole RNA Interference Radioligand Assay Receptors, Dopamine D2 Chemistry Time Factors Transfection Research Support, Non-U.S. Gov't |
| Content Type | Text |
| Resource Type | Article |
| Subject | Pharmacology |
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