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Mechanistic insights into dopaminergic and serotonergic neurotransmission – concerted interactions with helices 5 and 6 drive the functional outcome

Mechanistic insights into dopaminergic and serotonergic neurotransmission – concerted interactions with helices 5 and 6 drive the functional outcome

Chem Sci. 2021 Jul 2;12(33):10990-11003. doi: 10.1039/d1sc00749a. eCollection 2021 Aug 25.

Tomasz Maciej Stepniewski 1 2, Arturo Mancini 3, Richard Ågren 4, Mariona Torrens-Fontanals 1, Meriem Semache 3, Michel Bouvier 5 6, Kristoffer Sahlholm 4 7, Billy Breton 3 6, Jana Selent 1

Affiliations
1. Research Programme on Biomedical Informatics (GRIB), Hospital del Mar Medical Research Institute (IMIM) – Pompeu Fabra University (UPF) Dr Aiguader 88 Barcelona E-08003 Spain jana.selent@upf.edu.
2. InterAx Biotech AG, PARK InnovAARE 5234 Villigen Switzerland.
3. Domain Therapeutics NA Inc 7171 Frederick-Banting Saint-Laurent (QC) H4S 1Z9 Canada amancini@domaintherapeutics.com.
4. Department of Neuroscience, Karolinska Institute Stockholm Sweden.
5. Department of Biochemistry and Molecular Medicine, Université de Montréal Montreal QC H3C 3J7 Canada.
6. Institute for Research in Immunology and Cancer (IRIC), Université de Montréal Montréal Québec H3T 1J4 Canada.
7. Department of Integrative Medical Biology, Wallenberg Centre for Molecular Medicine, Umeå University 90187 Umeå Sweden.

Abstract

Brain functions rely on neurotransmitters that mediate communication between billions of neurons. Disruption of this communication can result in a plethora of psychiatric and neurological disorders. In this work, we combine molecular dynamics simulations, live-cell biosensor and electrophysiological assays to investigate the action of the neurotransmitter dopamine at the dopaminergic D2 receptor (D2R). The study of dopamine and closely related chemical probes reveals how neurotransmitter binding translates into the activation of distinct subsets of D2R effectors (i.e.: Gi2, GoB, Gz and β-arrestin 2). Ligand interactions with key residues in TM5 (S5.42) and TM6 (H6.55) in the D2R binding pocket yield a dopamine-like coupling signature, whereas exclusive TM5 interaction is typically linked to preferential G protein coupling (in particular GoB) over β-arrestin. Further experiments for serotonin receptors indicate that the reported molecular mechanism is shared by other monoaminergic neurotransmitter receptors. Ultimately, our study highlights how sequence variation in position 6.55 is used by nature to fine-tune β-arrestin recruitment and in turn receptor signaling and internalization of neurotransmitter receptors.

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