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

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dc.contributor.author Stepniewski, Tomasz Maciej, 1988-
dc.contributor.author Mancini, Arturo
dc.contributor.author Ågren, Richard
dc.contributor.author Torrens Fontanals, Mariona
dc.contributor.author Semache, Meriem
dc.contributor.author Bouvier, Michel
dc.contributor.author Sahlholm, Kristoffer
dc.contributor.author Breton, Billy
dc.contributor.author Selent, Jana
dc.date.accessioned 2021-10-18T06:38:05Z
dc.date.available 2021-10-18T06:38:05Z
dc.date.issued 2021
dc.identifier.citation Stepniewski TM, Mancini A, Ågren R, Torrens-Fontanals M, Semache M, Bouvier M, Sahlholm K, Breton B, Selent J. Mechanistic insights into dopaminergic and serotonergic neurotransmission - concerted interactions with helices 5 and 6 drive the functional outcome. Chem Sci. 2021;12(33):10990-11003. DOI: 10.1039/d1sc00749a
dc.identifier.issn 2041-6520
dc.identifier.uri http://hdl.handle.net/10230/48675
dc.description.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.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Royal Society of Chemistry
dc.relation.ispartof Chem Sci. 2021;12(33):10990-11003
dc.rights © Open Access Article. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.
dc.rights.uri http://creativecommons.org/licenses/by/3.0/
dc.title Mechanistic insights into dopaminergic and serotonergic neurotransmission - concerted interactions with helices 5 and 6 drive the functional outcome
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1039/d1sc00749a
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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