ArticleBiochimica et biophysica acta2014
NMR structures of the human α7 nAChR transmembrane domain and associated anesthetic binding sites.
Article in Biochimica et biophysica acta, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed.
- Mechanism of NACHO-mediated assembly of pentameric ligand-gated ion channels.bioRxiv : the preprint server for biology · 2024Article
- Unconventional PDZ Recognition Revealed in α7 nAChR-PICK1 Complexes.ACS chemical neuroscience · 2024Article
- Structural Elucidation of Ivermectin Binding to α7nAChR and the Induced Channel Desensitization.ACS chemical neuroscience · 2023Article
- Speculation on How RIC-3 and Other Chaperones Facilitate α7 Nicotinic Receptor Folding and Assembly.Molecules (Basel, Switzerland) · 2022Review
- Structures of highly flexible intracellular domain of human α7 nicotinic acetylcholine receptor.Nature communications · 2022Article
- Effects of General Anesthetics on Synaptic Transmission and Plasticity.Current neuropharmacology · 2022Review
- Different Classes of Antidepressants Inhibit the Rat α7 Nicotinic Acetylcholine Receptor by Interacting within the Ion Channel: A Functional and Structural Study.Molecules (Basel, Switzerland) · 2021Article
- In Silico Modeling of the α7 Nicotinic Acetylcholine Receptor: New Pharmacological Challenges Associated with Multiple Modes of Signaling.Mini reviews in medicinal chemistry · 2020Review
- Caenorhabditis elegans muscle Cys-loop receptors as novel targets of terpenoids with potential anthelmintic activity.PLoS neglected tropical diseases · 2019Article
- Triple arginines as molecular determinants for pentameric assembly of the intracellular domain of 5-HTThe Journal of general physiology · 2019Article
- Structural basis of neurosteroid anesthetic action on GABANature communications · 2018Article
- Anesthetic-sensitive ion channel modulation is associated with a molar water solubility cut-off.BMC pharmacology & toxicology · 2018Article
- Propofol inhibits the voltage-gated sodium channel NaChBac at multiple sites.The Journal of general physiology · 2018Article
- Solution NMR Studies of Anesthetic Interactions with Ion Channels.Methods in enzymology · 2018Article
- Recent progress on the molecular pharmacology of propofol.F1000Research · 2018Review
- X-Ray Crystallographic Studies for Revealing Binding Sites of General Anesthetics in Pentameric Ligand-Gated Ion Channels.Methods in enzymology · 2018Article
- Mapping General Anesthetic Sites in Heteromeric γ-Aminobutyric Acid Type A Receptors Reveals a Potential For Targeting Receptor Subtypes.Anesthesia and analgesia · 2016Review
- Functional Human α7 Nicotinic Acetylcholine Receptor (nAChR) Generated from Escherichia coli.The Journal of biological chemistry · 2016Article
- Pentameric quaternary structure of the intracellular domain of serotonin type 3A receptors.Scientific reports · 2016Article
- Common Anesthetic-binding Site for Inhibition of Pentameric Ligand-gated Ion Channels.Anesthesiology · 2016Article
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Authors and funding
6 authors.
Funding
Abstract
The α7 nicotinic acetylcholine receptor (nAChR), assembled as homomeric pentameric ligand-gated ion channels, is one of the most abundant nAChR subtypes in the brain. Despite its importance in memory, learning and cognition, no structure has been determined for the α7 nAChR TM domain, a target for allosteric modulators. Using solution state NMR, we determined the structure of the human α7 nAChR TM domain (PDB ID: 2MAW) and demonstrated that the α7 TM domain formed functional channels in Xenopus oocytes. We identified the associated binding sites for the anesthetics halothane and ketamine; the former cannot sensitively inhibit α7 function, but the latter can. The α7 TM domain folds into the expected four-helical bundle motif, but the intra-subunit cavity at the extracellular end of the α7 TM domain is smaller than the equivalent cavity in the α4β2 nAChRs (PDB IDs: 2LLY; 2LM2). Neither drug binds to the extracellular end of the α7 TM domain, but two halothane molecules or one ketamine molecule binds to the intracellular end of the α7 TM domain. Halothane and ketamine binding sites are partially overlapped. Ketamine, but not halothane, perturbed the α7 channel-gate residue L9'. Furthermore, halothane did not induce profound dynamics changes in the α7 channel as observed in α4β2. The study offers a novel high-resolution structure for the human α7 nAChR TM domain that is invaluable for developing α7-specific therapeutics. It also provides evidence to support the hypothesis: only when anesthetic binding perturbs the channel pore or alters the channel motion, can binding generate functional consequences.
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