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A Molecular Basis for Selective Antagonist Destabilization of Dopamine D(3) Receptor Quaternary Organization
The dopamine D(3) receptor (D(3)R) is a molecular target for both first-generation and several recently-developed antipsychotic agents. Following stable expression of this mEGFP-tagged receptor, Spatial Intensity Distribution Analysis indicated that a substantial proportion of the receptor was prese...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5437050/ https://www.ncbi.nlm.nih.gov/pubmed/28522847 http://dx.doi.org/10.1038/s41598-017-02249-3 |
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author | Marsango, Sara Caltabiano, Gianluigi Jiménez-Rosés, Mireia Millan, Mark J. Pediani, John D. Ward, Richard J. Milligan, Graeme |
author_facet | Marsango, Sara Caltabiano, Gianluigi Jiménez-Rosés, Mireia Millan, Mark J. Pediani, John D. Ward, Richard J. Milligan, Graeme |
author_sort | Marsango, Sara |
collection | PubMed |
description | The dopamine D(3) receptor (D(3)R) is a molecular target for both first-generation and several recently-developed antipsychotic agents. Following stable expression of this mEGFP-tagged receptor, Spatial Intensity Distribution Analysis indicated that a substantial proportion of the receptor was present within dimeric/oligomeric complexes and that increased expression levels of the receptor favored a greater dimer to monomer ratio. Addition of the antipsychotics, spiperone or haloperidol, resulted in re-organization of D(3)R quaternary structure to promote monomerization. This action was dependent on ligand concentration and reversed upon drug washout. By contrast, a number of other antagonists with high affinity at the D(3)R, did not alter the dimer/monomer ratio. Molecular dynamics simulations following docking of each of the ligands into a model of the D(3)R derived from the available atomic level structure, and comparisons to the receptor in the absence of ligand, were undertaken. They showed that, in contrast to the other antagonists, spiperone and haloperidol respectively increased the atomic distance between reference α carbon atoms of transmembrane domains IV and V and I and II, both of which provide key interfaces for D(3)R dimerization. These results offer a molecular explanation for the distinctive ability of spiperone and haloperidol to disrupt D(3)R dimerization. |
format | Online Article Text |
id | pubmed-5437050 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-54370502017-05-19 A Molecular Basis for Selective Antagonist Destabilization of Dopamine D(3) Receptor Quaternary Organization Marsango, Sara Caltabiano, Gianluigi Jiménez-Rosés, Mireia Millan, Mark J. Pediani, John D. Ward, Richard J. Milligan, Graeme Sci Rep Article The dopamine D(3) receptor (D(3)R) is a molecular target for both first-generation and several recently-developed antipsychotic agents. Following stable expression of this mEGFP-tagged receptor, Spatial Intensity Distribution Analysis indicated that a substantial proportion of the receptor was present within dimeric/oligomeric complexes and that increased expression levels of the receptor favored a greater dimer to monomer ratio. Addition of the antipsychotics, spiperone or haloperidol, resulted in re-organization of D(3)R quaternary structure to promote monomerization. This action was dependent on ligand concentration and reversed upon drug washout. By contrast, a number of other antagonists with high affinity at the D(3)R, did not alter the dimer/monomer ratio. Molecular dynamics simulations following docking of each of the ligands into a model of the D(3)R derived from the available atomic level structure, and comparisons to the receptor in the absence of ligand, were undertaken. They showed that, in contrast to the other antagonists, spiperone and haloperidol respectively increased the atomic distance between reference α carbon atoms of transmembrane domains IV and V and I and II, both of which provide key interfaces for D(3)R dimerization. These results offer a molecular explanation for the distinctive ability of spiperone and haloperidol to disrupt D(3)R dimerization. Nature Publishing Group UK 2017-05-18 /pmc/articles/PMC5437050/ /pubmed/28522847 http://dx.doi.org/10.1038/s41598-017-02249-3 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Marsango, Sara Caltabiano, Gianluigi Jiménez-Rosés, Mireia Millan, Mark J. Pediani, John D. Ward, Richard J. Milligan, Graeme A Molecular Basis for Selective Antagonist Destabilization of Dopamine D(3) Receptor Quaternary Organization |
title | A Molecular Basis for Selective Antagonist Destabilization of Dopamine D(3) Receptor Quaternary Organization |
title_full | A Molecular Basis for Selective Antagonist Destabilization of Dopamine D(3) Receptor Quaternary Organization |
title_fullStr | A Molecular Basis for Selective Antagonist Destabilization of Dopamine D(3) Receptor Quaternary Organization |
title_full_unstemmed | A Molecular Basis for Selective Antagonist Destabilization of Dopamine D(3) Receptor Quaternary Organization |
title_short | A Molecular Basis for Selective Antagonist Destabilization of Dopamine D(3) Receptor Quaternary Organization |
title_sort | molecular basis for selective antagonist destabilization of dopamine d(3) receptor quaternary organization |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5437050/ https://www.ncbi.nlm.nih.gov/pubmed/28522847 http://dx.doi.org/10.1038/s41598-017-02249-3 |
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