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; Scammells, Peter J.; Capuano, Ben; Abramyan, Ara M; Thal, David M.; Javitch, Jonathan A.; Christopoulos, Arthur; Shi, Lei; Lane, J. Robert

Abstract

© 2018 The Author(s). Sodiumions (Na+) allosterically modulate the binding of orthosteric agonists and antagonists to many class A G protein-coupled receptors, including the dopamine D 2 receptor (D 2 R). 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 D 2 R 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 D 2 R, providing opportunities for fine-tuning of modulatory effects in future allosteric drug design efforts.

Citation

Draper-Joyce, C. J., Verma, R. K., Michino, M., Shonberg, J., Kopinathan, A., Herenbrink, C., Scammells, P. J., Capuano, B., Abramyan, A. M., Thal, D. M., Javitch, J. A., Christopoulos, A., Shi, L., & Lane, J. R. (2018). The action of a negative allosteric modulator at the dopamine D2 receptor is dependent upon sodium ions. Scientific Reports, 8(1), Article 1208. https://doi.org/10.1038/s41598-018-19642-1

• Journal Article Type: Article
• Acceptance Date: Dec 19, 2017
• Online Publication Date: Jan 19, 2018
• Publication Date: Jan 19, 2018
• Deposit Date: Apr 22, 2020
• Publicly Available Date: Jun 8, 2020
• Journal: Scientific Reports
• Electronic ISSN: 2045-2322
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 8
• Issue: 1
• Article Number: 1208
• DOI: https://doi.org/10.1038/s41598-018-19642-1
• Public URL: https://nottingham-repository.worktribe.com/output/1339362
• Publisher URL: https://www.nature.com/articles/s41598-018-19642-1