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Pathways and Barriers for Ion Translocation through the 5-HT(3)A Receptor Channel

Pentameric ligand gated ion channels (pLGICs) are ionotropic receptors that mediate fast intercellular communications at synaptic level and include either cation selective (e.g., nAChR and 5-HT(3)) or anion selective (e.g., GlyR, GABA(A) and GluCl) membrane channels. Among others, 5-HT(3) is one of...

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Autores principales: Di Maio, Danilo, Chandramouli, Balasubramanian, Brancato, Giuseppe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4605793/
https://www.ncbi.nlm.nih.gov/pubmed/26465896
http://dx.doi.org/10.1371/journal.pone.0140258
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author Di Maio, Danilo
Chandramouli, Balasubramanian
Brancato, Giuseppe
author_facet Di Maio, Danilo
Chandramouli, Balasubramanian
Brancato, Giuseppe
author_sort Di Maio, Danilo
collection PubMed
description Pentameric ligand gated ion channels (pLGICs) are ionotropic receptors that mediate fast intercellular communications at synaptic level and include either cation selective (e.g., nAChR and 5-HT(3)) or anion selective (e.g., GlyR, GABA(A) and GluCl) membrane channels. Among others, 5-HT(3) is one of the most studied members, since its first cloning back in 1991, and a large number of studies have successfully pinpointed protein residues critical for its activation and channel gating. In addition, 5-HT(3) is also the target of a few pharmacological treatments due to the demonstrated benefits of its modulation in clinical trials. Nonetheless, a detailed molecular analysis of important protein features, such as the origin of its ion selectivity and the rather low conductance as compared to other channel homologues, has been unfeasible until the recent crystallization of the mouse 5-HT(3)A receptor. Here, we present extended molecular dynamics simulations and free energy calculations of the whole 5-HT(3)A protein with the aim of better understanding its ion transport properties, such as the pathways for ion permeation into the receptor body and the complex nature of the selectivity filter. Our investigation unravels previously unpredicted structural features of the 5-HT(3)A receptor, such as the existence of alternative intersubunit pathways for ion translocation at the interface between the extracellular and the transmembrane domains, in addition to the one along the channel main axis. Moreover, our study offers a molecular interpretation of the role played by an arginine triplet located in the intracellular domain on determining the characteristic low conductance of the 5-HT(3)A receptor, as evidenced in previous experiments. In view of these results, possible implications on other members of the superfamily are suggested.
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spelling pubmed-46057932015-10-29 Pathways and Barriers for Ion Translocation through the 5-HT(3)A Receptor Channel Di Maio, Danilo Chandramouli, Balasubramanian Brancato, Giuseppe PLoS One Research Article Pentameric ligand gated ion channels (pLGICs) are ionotropic receptors that mediate fast intercellular communications at synaptic level and include either cation selective (e.g., nAChR and 5-HT(3)) or anion selective (e.g., GlyR, GABA(A) and GluCl) membrane channels. Among others, 5-HT(3) is one of the most studied members, since its first cloning back in 1991, and a large number of studies have successfully pinpointed protein residues critical for its activation and channel gating. In addition, 5-HT(3) is also the target of a few pharmacological treatments due to the demonstrated benefits of its modulation in clinical trials. Nonetheless, a detailed molecular analysis of important protein features, such as the origin of its ion selectivity and the rather low conductance as compared to other channel homologues, has been unfeasible until the recent crystallization of the mouse 5-HT(3)A receptor. Here, we present extended molecular dynamics simulations and free energy calculations of the whole 5-HT(3)A protein with the aim of better understanding its ion transport properties, such as the pathways for ion permeation into the receptor body and the complex nature of the selectivity filter. Our investigation unravels previously unpredicted structural features of the 5-HT(3)A receptor, such as the existence of alternative intersubunit pathways for ion translocation at the interface between the extracellular and the transmembrane domains, in addition to the one along the channel main axis. Moreover, our study offers a molecular interpretation of the role played by an arginine triplet located in the intracellular domain on determining the characteristic low conductance of the 5-HT(3)A receptor, as evidenced in previous experiments. In view of these results, possible implications on other members of the superfamily are suggested. Public Library of Science 2015-10-14 /pmc/articles/PMC4605793/ /pubmed/26465896 http://dx.doi.org/10.1371/journal.pone.0140258 Text en © 2015 Di Maio et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Di Maio, Danilo
Chandramouli, Balasubramanian
Brancato, Giuseppe
Pathways and Barriers for Ion Translocation through the 5-HT(3)A Receptor Channel
title Pathways and Barriers for Ion Translocation through the 5-HT(3)A Receptor Channel
title_full Pathways and Barriers for Ion Translocation through the 5-HT(3)A Receptor Channel
title_fullStr Pathways and Barriers for Ion Translocation through the 5-HT(3)A Receptor Channel
title_full_unstemmed Pathways and Barriers for Ion Translocation through the 5-HT(3)A Receptor Channel
title_short Pathways and Barriers for Ion Translocation through the 5-HT(3)A Receptor Channel
title_sort pathways and barriers for ion translocation through the 5-ht(3)a receptor channel
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4605793/
https://www.ncbi.nlm.nih.gov/pubmed/26465896
http://dx.doi.org/10.1371/journal.pone.0140258
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