A molecular basis for selective antagonist destabilization of dopamine D3 receptor quaternary organization

Marsango, S., Caltabiano, G., Jiménez-Rosés, M., Millan, M. J., Pediani, J. D. , Ward, R. J. and Milligan, G. (2017) A molecular basis for selective antagonist destabilization of dopamine D3 receptor quaternary organization. Scientific Reports, 7, 2134. (doi: 10.1038/s41598-017-02249-3) (PMID:28522847) (PMCID:PMC5437050)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Pediani, Dr John and Ward, Dr Richard and Millan, Dr Mark and Caltabiano, Dr Gianluigi and Milligan, Professor Graeme and Marsango, Dr Sara
Authors: Marsango, S., Caltabiano, G., Jiménez-Rosés, M., Millan, M. J., Pediani, J. D., Ward, R. J., and Milligan, G.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
Journal Name:Scientific Reports
Publisher:Nature Publishing Group
ISSN:2045-2322
ISSN (Online):2045-2322
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Scientific Reports 7:2134.
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
656901The organisational structure of class A GPCRs: Implications for pharmacology, function and therapeutic regulationGraeme MilliganMedical Research Council (MRC)MR/L023806/1RI MOLECULAR CELL & SYSTEMS BIOLOGY