ArticleThe Journal of biological chemistry2016
A Novel Bifunctional Alkylphenol Anesthetic Allows Characterization of γ-Aminobutyric Acid, Type A (GABAA), Receptor Subunit Binding Selectivity in Synaptosomes.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 35 citations in OpenAlex.
- General anesthetic modulation of a pentameric ligand-gated ion channel explored with simulations.Biophysical journal · 2026Article
- Biophysical insights into a cryptic ligand site in the hydrophobic core of human PCNA.Biophysical journal · 2026Article
- Median effective dose of fospropofol disodium for suppression of the cough reflex during tracheostomy tube exchange in patients with disorders of consciousness receiving fixed-dose sufentanil.Frontiers in pharmacology · 2026Article
- Functionalization of 1,3-Diisopropylbenzene to Probe the Antagonism of Propofol Anesthesia.ACS chemical neuroscience · 2025Article
- Sedative-hypnotic properties and mitochondrial effects of coenzyme Q2 in mice.Current molecular pharmacology · 2025Article
- Synapse-Specific Trapping of SNARE Machinery Proteins in the AnesthetizedThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Alchemical Free Energy Calculations on Membrane-Associated Proteins.Journal of chemical theory and computation · 2023Review
- Structure-function Studies of GABA (A) Receptors and Related computer-aided Studies.Journal of molecular neuroscience : MN · 2023Review
- Mechanistic basis of propofol-induced disruption of kinesin processivity.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Substrate-Dependent Modulation of SIRT2 by a Fluorescent Probe, 1-Aminoanthracene.Biochemistry · 2020Article
- Computational Methods for the Identification of Molecular Targets of Toxic Food Additives. Butylated Hydroxytoluene as a Case Study.Molecules (Basel, Switzerland) · 2020Article
- Azi-medetomidine: Synthesis and Characterization of a Novel α2 Adrenergic Photoaffinity Ligand.ACS chemical neuroscience · 2019Article
- Towards a Comprehensive Understanding of Anesthetic Mechanisms of Action: A Decade of Discovery.Trends in pharmacological sciences · 2019Review
- Multiscale Simulations of Biological Membranes: The Challenge To Understand Biological Phenomena in a Living Substance.Chemical reviews · 2019Article
- Alkylphenol inverse agonists of HCN1 gating: H-bond propensity, ring saturation and adduct geometry differentially determine efficacy and potency.Biochemical pharmacology · 2019Article
- A Streamlined, General Approach for Computing Ligand Binding Free Energies and Its Application to GPCR-Bound Cholesterol.Journal of chemical theory and computation · 2018Article
- Allosteric potentiation of a ligand-gated ion channel is mediated by access to a deep membrane-facing cavity.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Identification of binding sites contributing to volatile anesthetic effects on GABA type A receptors.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2018Article
- Recent progress on the molecular pharmacology of propofol.F1000Research · 2018Review
- Optoanesthesia: Use of Anesthetic Photolabels In Vivo.Methods in enzymology · 2018Article
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
Abstract
Propofol, an intravenous anesthetic, is a positive modulator of the GABAA receptor, but the mechanistic details, including the relevant binding sites and alternative targets, remain disputed. Here we undertook an in-depth study of alkylphenol-based anesthetic binding to synaptic membranes. We designed, synthesized, and characterized a chemically active alkylphenol anesthetic (2-((prop-2-yn-1-yloxy)methyl)-5-(3-(trifluoromethyl)-3H-diazirin-3-yl)phenol, AziPm-click (1)), for affinity-based protein profiling (ABPP) of propofol-binding proteins in their native state within mouse synaptosomes. The ABPP strategy captured ∼4% of the synaptosomal proteome, including the unbiased capture of five α or β GABAA receptor subunits. Lack of γ2 subunit capture was not due to low abundance. Consistent with this, independent molecular dynamics simulations with alchemical free energy perturbation calculations predicted selective propofol binding to interfacial sites, with higher affinities for α/β than γ-containing interfaces. The simulations indicated hydrogen bonding is a key component leading to propofol-selective binding within GABAA receptor subunit interfaces, with stable hydrogen bonds observed between propofol and α/β cavity residues but not γ cavity residues. We confirmed this by introducing a hydrogen bond-null propofol analogue as a protecting ligand for targeted-ABPP and observed a lack of GABAA receptor subunit protection. This investigation demonstrates striking interfacial GABAA receptor subunit selectivity in the native milieu, suggesting that asymmetric occupancy of heteropentameric ion channels by alkylphenol-based anesthetics is sufficient to induce modulation of activity.
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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.