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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...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2015
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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. |
format | Online Article Text |
id | pubmed-4605793 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
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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