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Mechanistic Insights into the Allosteric Modulation of Opioid Receptors by Sodium Ions
[Image: see text] The idea of sodium ions altering G-protein-coupled receptor (GPCR) ligand binding and signaling was first suggested for opioid receptors (ORs) in the 1970s and subsequently extended to other GPCRs. Recently published ultra-high-resolution crystal structures of GPCRs, including that...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American
Chemical Society
2014
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4131901/ https://www.ncbi.nlm.nih.gov/pubmed/25073009 http://dx.doi.org/10.1021/bi5006915 |
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author | Shang, Yi LeRouzic, Valerie Schneider, Sebastian Bisignano, Paola Pasternak, Gavril W. Filizola, Marta |
author_facet | Shang, Yi LeRouzic, Valerie Schneider, Sebastian Bisignano, Paola Pasternak, Gavril W. Filizola, Marta |
author_sort | Shang, Yi |
collection | PubMed |
description | [Image: see text] The idea of sodium ions altering G-protein-coupled receptor (GPCR) ligand binding and signaling was first suggested for opioid receptors (ORs) in the 1970s and subsequently extended to other GPCRs. Recently published ultra-high-resolution crystal structures of GPCRs, including that of the δ-OR subtype, have started to shed light on the mechanism underlying sodium control in GPCR signaling by revealing details of the sodium binding site. Whether sodium accesses different receptor subtypes from the extra- or intracellular sides, following similar or different pathways, is still an open question. Earlier experiments in brain homogenates suggested a differential sodium regulation of ligand binding to the three major OR subtypes, in spite of their high degree of sequence similarity. Intrigued by this possibility, we explored the dynamic nature of sodium binding to δ-OR, μ-OR, and κ-OR by means of microsecond-scale, all-atom molecular dynamics (MD) simulations. Rapid sodium permeation was observed exclusively from the extracellular milieu, and following similar binding pathways in all three ligand-free OR systems, notwithstanding extra densities of sodium observed near nonconserved residues of κ-OR and δ-OR, but not in μ-OR. We speculate that these differences may be responsible for the differential increase in antagonist binding affinity of μ-OR by sodium resulting from specific ligand binding experiments in transfected cells. On the other hand, sodium reduced the level of binding of subtype-specific agonists to all OR subtypes. Additional biased and unbiased MD simulations were conducted using the δ-OR ultra-high-resolution crystal structure as a model system to provide a mechanistic explanation for this experimental observation. |
format | Online Article Text |
id | pubmed-4131901 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | American
Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-41319012015-07-21 Mechanistic Insights into the Allosteric Modulation of Opioid Receptors by Sodium Ions Shang, Yi LeRouzic, Valerie Schneider, Sebastian Bisignano, Paola Pasternak, Gavril W. Filizola, Marta Biochemistry [Image: see text] The idea of sodium ions altering G-protein-coupled receptor (GPCR) ligand binding and signaling was first suggested for opioid receptors (ORs) in the 1970s and subsequently extended to other GPCRs. Recently published ultra-high-resolution crystal structures of GPCRs, including that of the δ-OR subtype, have started to shed light on the mechanism underlying sodium control in GPCR signaling by revealing details of the sodium binding site. Whether sodium accesses different receptor subtypes from the extra- or intracellular sides, following similar or different pathways, is still an open question. Earlier experiments in brain homogenates suggested a differential sodium regulation of ligand binding to the three major OR subtypes, in spite of their high degree of sequence similarity. Intrigued by this possibility, we explored the dynamic nature of sodium binding to δ-OR, μ-OR, and κ-OR by means of microsecond-scale, all-atom molecular dynamics (MD) simulations. Rapid sodium permeation was observed exclusively from the extracellular milieu, and following similar binding pathways in all three ligand-free OR systems, notwithstanding extra densities of sodium observed near nonconserved residues of κ-OR and δ-OR, but not in μ-OR. We speculate that these differences may be responsible for the differential increase in antagonist binding affinity of μ-OR by sodium resulting from specific ligand binding experiments in transfected cells. On the other hand, sodium reduced the level of binding of subtype-specific agonists to all OR subtypes. Additional biased and unbiased MD simulations were conducted using the δ-OR ultra-high-resolution crystal structure as a model system to provide a mechanistic explanation for this experimental observation. American Chemical Society 2014-07-21 2014-08-12 /pmc/articles/PMC4131901/ /pubmed/25073009 http://dx.doi.org/10.1021/bi5006915 Text en Copyright © 2014 American Chemical Society Terms of Use (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) |
spellingShingle | Shang, Yi LeRouzic, Valerie Schneider, Sebastian Bisignano, Paola Pasternak, Gavril W. Filizola, Marta Mechanistic Insights into the Allosteric Modulation of Opioid Receptors by Sodium Ions |
title | Mechanistic Insights into
the Allosteric Modulation
of Opioid Receptors by Sodium Ions |
title_full | Mechanistic Insights into
the Allosteric Modulation
of Opioid Receptors by Sodium Ions |
title_fullStr | Mechanistic Insights into
the Allosteric Modulation
of Opioid Receptors by Sodium Ions |
title_full_unstemmed | Mechanistic Insights into
the Allosteric Modulation
of Opioid Receptors by Sodium Ions |
title_short | Mechanistic Insights into
the Allosteric Modulation
of Opioid Receptors by Sodium Ions |
title_sort | mechanistic insights into
the allosteric modulation
of opioid receptors by sodium ions |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4131901/ https://www.ncbi.nlm.nih.gov/pubmed/25073009 http://dx.doi.org/10.1021/bi5006915 |
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