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

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...

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Autores principales: Stepniewski, Tomasz Maciej, Mancini, Arturo, Ågren, Richard, Torrens-Fontanals, Mariona, Semache, Meriem, Bouvier, Michel, Sahlholm, Kristoffer, Breton, Billy, Selent, Jana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society of Chemistry 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386650/
https://www.ncbi.nlm.nih.gov/pubmed/34522296
http://dx.doi.org/10.1039/d1sc00749a
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author Stepniewski, Tomasz Maciej
Mancini, Arturo
Ågren, Richard
Torrens-Fontanals, Mariona
Semache, Meriem
Bouvier, Michel
Sahlholm, Kristoffer
Breton, Billy
Selent, Jana
author_facet Stepniewski, Tomasz Maciej
Mancini, Arturo
Ågren, Richard
Torrens-Fontanals, Mariona
Semache, Meriem
Bouvier, Michel
Sahlholm, Kristoffer
Breton, Billy
Selent, Jana
author_sort Stepniewski, Tomasz Maciej
collection PubMed
description 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 D(2) receptor (D(2)R). The study of dopamine and closely related chemical probes reveals how neurotransmitter binding translates into the activation of distinct subsets of D(2)R effectors (i.e.: G(i2), G(oB), G(z) and β-arrestin 2). Ligand interactions with key residues in TM5 (S5.42) and TM6 (H6.55) in the D(2)R binding pocket yield a dopamine-like coupling signature, whereas exclusive TM5 interaction is typically linked to preferential G protein coupling (in particular G(oB)) 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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spelling pubmed-83866502021-09-13 Mechanistic insights into dopaminergic and serotonergic neurotransmission – concerted interactions with helices 5 and 6 drive the functional outcome Stepniewski, Tomasz Maciej Mancini, Arturo Ågren, Richard Torrens-Fontanals, Mariona Semache, Meriem Bouvier, Michel Sahlholm, Kristoffer Breton, Billy Selent, Jana Chem Sci Chemistry 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 D(2) receptor (D(2)R). The study of dopamine and closely related chemical probes reveals how neurotransmitter binding translates into the activation of distinct subsets of D(2)R effectors (i.e.: G(i2), G(oB), G(z) and β-arrestin 2). Ligand interactions with key residues in TM5 (S5.42) and TM6 (H6.55) in the D(2)R binding pocket yield a dopamine-like coupling signature, whereas exclusive TM5 interaction is typically linked to preferential G protein coupling (in particular G(oB)) 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. The Royal Society of Chemistry 2021-07-02 /pmc/articles/PMC8386650/ /pubmed/34522296 http://dx.doi.org/10.1039/d1sc00749a Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by/3.0/
spellingShingle Chemistry
Stepniewski, Tomasz Maciej
Mancini, Arturo
Ågren, Richard
Torrens-Fontanals, Mariona
Semache, Meriem
Bouvier, Michel
Sahlholm, Kristoffer
Breton, Billy
Selent, Jana
Mechanistic insights into dopaminergic and serotonergic neurotransmission – concerted interactions with helices 5 and 6 drive the functional outcome
title Mechanistic insights into dopaminergic and serotonergic neurotransmission – concerted interactions with helices 5 and 6 drive the functional outcome
title_full Mechanistic insights into dopaminergic and serotonergic neurotransmission – concerted interactions with helices 5 and 6 drive the functional outcome
title_fullStr Mechanistic insights into dopaminergic and serotonergic neurotransmission – concerted interactions with helices 5 and 6 drive the functional outcome
title_full_unstemmed Mechanistic insights into dopaminergic and serotonergic neurotransmission – concerted interactions with helices 5 and 6 drive the functional outcome
title_short Mechanistic insights into dopaminergic and serotonergic neurotransmission – concerted interactions with helices 5 and 6 drive the functional outcome
title_sort mechanistic insights into dopaminergic and serotonergic neurotransmission – concerted interactions with helices 5 and 6 drive the functional outcome
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386650/
https://www.ncbi.nlm.nih.gov/pubmed/34522296
http://dx.doi.org/10.1039/d1sc00749a
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