A Molecular Basis for Selective Antagonist Destabilization of Dopamine D3 Receptor Quaternary Organization

Abstract The dopamine D3 receptor (D3R) 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...

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Autores principales:	Sara Marsango, Gianluigi Caltabiano, Mireia Jiménez-Rosés, Mark J. Millan, John D. Pediani, Richard J. Ward, Graeme Milligan
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3470a476fb0447e9a1e204628cce051b
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spelling	oai:doaj.org-article:3470a476fb0447e9a1e204628cce051b2021-12-02T11:53:07ZA Molecular Basis for Selective Antagonist Destabilization of Dopamine D3 Receptor Quaternary Organization10.1038/s41598-017-02249-32045-2322https://doaj.org/article/3470a476fb0447e9a1e204628cce051b2017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02249-3https://doaj.org/toc/2045-2322Abstract The dopamine D3 receptor (D3R) 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 D3R 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 D3R, did not alter the dimer/monomer ratio. Molecular dynamics simulations following docking of each of the ligands into a model of the D3R 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 D3R dimerization. These results offer a molecular explanation for the distinctive ability of spiperone and haloperidol to disrupt D3R dimerization.Sara MarsangoGianluigi CaltabianoMireia Jiménez-RosésMark J. MillanJohn D. PedianiRichard J. WardGraeme MilliganNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-17 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sara Marsango Gianluigi Caltabiano Mireia Jiménez-Rosés Mark J. Millan John D. Pediani Richard J. Ward Graeme Milligan A Molecular Basis for Selective Antagonist Destabilization of Dopamine D3 Receptor Quaternary Organization
description	Abstract The dopamine D3 receptor (D3R) 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 D3R 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 D3R, did not alter the dimer/monomer ratio. Molecular dynamics simulations following docking of each of the ligands into a model of the D3R 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 D3R dimerization. These results offer a molecular explanation for the distinctive ability of spiperone and haloperidol to disrupt D3R dimerization.
format	article
author	Sara Marsango Gianluigi Caltabiano Mireia Jiménez-Rosés Mark J. Millan John D. Pediani Richard J. Ward Graeme Milligan
author_facet	Sara Marsango Gianluigi Caltabiano Mireia Jiménez-Rosés Mark J. Millan John D. Pediani Richard J. Ward Graeme Milligan
author_sort	Sara Marsango
title	A Molecular Basis for Selective Antagonist Destabilization of Dopamine D3 Receptor Quaternary Organization
title_short	A Molecular Basis for Selective Antagonist Destabilization of Dopamine D3 Receptor Quaternary Organization
title_full	A Molecular Basis for Selective Antagonist Destabilization of Dopamine D3 Receptor Quaternary Organization
title_fullStr	A Molecular Basis for Selective Antagonist Destabilization of Dopamine D3 Receptor Quaternary Organization
title_full_unstemmed	A Molecular Basis for Selective Antagonist Destabilization of Dopamine D3 Receptor Quaternary Organization
title_sort	molecular basis for selective antagonist destabilization of dopamine d3 receptor quaternary organization
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/3470a476fb0447e9a1e204628cce051b
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A Molecular Basis for Selective Antagonist Destabilization of Dopamine D3 Receptor Quaternary Organization

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