ArticleBiochemistry2014
Mechanistic insights into the allosteric modulation of opioid receptors by sodium ions.
Article in Biochemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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Who cites it
58 citing papers in PubMed, 101 citations in OpenAlex.
- Structure-guided allosteric modulation of the delta opioid receptor.Nature communications · 2026Article
- Structure-Bias Relationship of μ-Opioid Receptor Agonists.Handbook of experimental pharmacology · 2026Review
- Molecular Glues: A New Approach to Modulating GPCR Signaling Bias.Biochemistry · 2025Review
- Intracellular Pocket Conformations Determine Signaling Efficacy through the μ Opioid Receptor.Journal of chemical information and modeling · 2025Article
- Intracellular pocket conformations determine signaling efficacy through thebioRxiv : the preprint server for biology · 2024Article
- Article
- IUPHAR themed review: Opioid efficacy, bias, and selectivity.Pharmacological research · 2023Review
- Bringing GPCR Structural Biology to Medical Applications: Insights from Both V2 Vasopressin and Mu-Opioid Receptors.Membranes · 2023Review
- Molecular Dynamics Simulations of Ion Permeation in Human Voltage-Gated Sodium Channels.Journal of chemical theory and computation · 2023Article
- Three-Dimensional Structural Insights Have Revealed the Distinct Binding Interactions of Agonists, Partial Agonists, and Antagonists with the µ Opioid Receptor.International journal of molecular sciences · 2023Review
- Deep Learning Dynamic Allostery of G-Protein-Coupled Receptors.Research square · 2023Article
- Deep Learning Dynamic Allostery of G-Protein-Coupled Receptors.bioRxiv : the preprint server for biology · 2023Article
- Homology Modeling of the G Protein-Coupled Receptors.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Molecular Basis of Inhibitory Mechanism of Naltrexone and Its Metabolites through Structural and Energetic Analyses.Molecules (Basel, Switzerland) · 2022Article
- Unique features of different classes of G-protein-coupled receptors revealed from sequence coevolutionary and structural analysis.Proteins · 2022Article
- Evolutionary information helps understand distinctive features of the angiotensin II receptors AT1 and AT2 in amniota.PLoS computational biology · 2022Article
- Structural Characterization of KOR Inactive and Active States for 3D Pharmacology and Drug Discovery.Handbook of experimental pharmacology · 2022Review
- G protein signaling-biased mu opioid receptor agonists that produce sustained G protein activation are noncompetitive agonists.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Universal Properties and Specificities of the βInternational journal of molecular sciences · 2021Article
- Correlated Motions of Conserved Polar Motifs Lay out a Plausible Mechanism of G Protein-Coupled Receptor Activation.Biomolecules · 2021Article
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.