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The action of a negative allosteric modulator at the dopamine D2 receptor is dependent upon sodium ions

Draper-Joyce, Christopher J.; Verma, Ravi Kumar; Michino, Mayako; Shonberg, Jeremy; Kopinathan, Anitha; Herenbrink, Carmen Klein; Scammells, Peter J.; Capuano, Ben; Abramyan, Ara M; Thal, David M.; Javitch, Jonathan A.; Christopoulos, Arthur; Shi, Lei; Lane, J. Robert

Authors

Christopher J. Draper-Joyce

Ravi Kumar Verma

Mayako Michino

Jeremy Shonberg

Anitha Kopinathan

Carmen Klein Herenbrink

Peter J. Scammells

Ben Capuano

Ara M Abramyan

David M. Thal

Jonathan A. Javitch

Arthur Christopoulos

Lei Shi

ROB LANE ROB.LANE@NOTTINGHAM.AC.UK
Associate Professor



Abstract

Sodium ions (Na+) allosterically modulate the binding of orthosteric agonists and antagonists to many class A G protein-coupled receptors, including the dopamine D2 receptor (D2R). Experimental and computational evidences have revealed that this effect is mediated by the binding of Na+ to a conserved site located beneath the orthosteric binding site (OBS). SB269652 acts as a negative allosteric modulator (NAM) of the D2R that adopts an extended bitopic pose, in which the tetrahydroisoquinoline moiety interacts with the OBS and the indole-2-carboxamide moiety occupies a secondary binding pocket (SBP). In this study, we find that the presence of a Na+ within the conserved Na+-binding pocket is required for the action of SB269652. Using fragments of SB269652 and novel full-length analogues, we show that Na+ is required for the high affinity binding of the tetrahydroisoquinoline moiety within the OBS, and that the interaction of the indole-2-carboxamide moiety with the SBP determines the degree of Na+-sensitivity. Thus, we extend our understanding of the mode of action of this novel class of NAM by showing it acts synergistically with Na+ to modulate the binding of orthosteric ligands at the D2R, providing opportunities for fine-tuning of modulatory effects in future allosteric drug design efforts.

Journal Article Type Article
Publication Date Jan 19, 2018
Journal Scientific Reports
Print ISSN 2045-2322
Electronic ISSN 2045-2322
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 8
Article Number 1208
APA6 Citation Draper-Joyce, C. J., Verma, R. K., Michino, M., Shonberg, J., Kopinathan, A., Herenbrink, C. K., …Lane, J. R. (2018). The action of a negative allosteric modulator at the dopamine D2 receptor is dependent upon sodium ions. Scientific Reports, 8, https://doi.org/10.1038/s41598-018-19642-1
DOI https://doi.org/10.1038/s41598-018-19642-1
Publisher URL https://www.nature.com/articles/s41598-018-19642-1

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