ArticleProceedings of the National Academy of Sciences of the United States of America2018
Structural basis for the ethanol action on G-protein-activated inwardly rectifying potassium channel 1 revealed by NMR spectroscopy.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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8 citing papers in PubMed, 11 citations in OpenAlex.
- Blood Vessels as a Key Mediator for Ethanol Toxicity: Implication for Neuronal Damage.Life (Basel, Switzerland) · 2022Review
- Function-Related Dynamics in Multi-Spanning Helical Membrane Proteins Revealed by Solution NMR.Membranes · 2021Review
- The Lipid Activation Mechanism of a Transmembrane Potassium Channel.Journal of the American Chemical Society · 2020Article
- Codon Harmonization of a Kir3.1-KirBac1.3 Chimera for Structural Study Optimization.Biomolecules · 2020Article
- Conformational equilibrium defines the variable induction of the multidrug-binding transcriptional repressor QacR.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Site-Resolved and Quantitative Characterization of Very Weak Protein-Ligand Interactions.ACS chemical biology · 2019Article
- Discovery and Characterization of VU0529331, a Synthetic Small-Molecule Activator of Homomeric G Protein-Gated, Inwardly Rectifying, Potassium (GIRK) Channels.ACS chemical neuroscience · 2019Article
- The intriguing effect of ethanol and nicotine on acetylcholine-sensitive potassium current IKAch: Insight from a quantitative model.PloS one · 2019Article
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Ethanol consumption leads to a wide range of pharmacological effects by acting on the signaling proteins in the human nervous system, such as ion channels. Despite its familiarity and biological importance, very little is known about the molecular mechanisms underlying the ethanol action, due to extremely weak binding affinity and the dynamic nature of the ethanol interaction. In this research, we focused on the primary in vivo target of ethanol, G-protein-activated inwardly rectifying potassium channel (GIRK), which is responsible for the ethanol-induced analgesia. By utilizing solution NMR spectroscopy, we characterized the changes in the structure and dynamics of GIRK induced by ethanol binding. We demonstrated here that ethanol binds to GIRK with an apparent dissociation constant of 1.0 M and that the actual physiological binding site of ethanol is located on the cavity formed between the neighboring cytoplasmic regions of the GIRK tetramer. From the methyl-based NMR relaxation analyses, we revealed that ethanol activates GIRK by shifting the conformational equilibrium processes, which are responsible for the gating of GIRK, to stabilize an open conformation of the cytoplasmic ion gate. We suggest that the dynamic molecular mechanism of the ethanol-induced activation of GIRK represents a general model of the ethanol action on signaling proteins in the human nervous system.
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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.