ArticleProceedings of the National Academy of Sciences of the United States of America2025
Hidden complexity of α7 nicotinic acetylcholine receptor desensitization revealed by MD simulations and Markov state modeling.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Characterization of an open-channel structure and lateral conduction pathway in the cation-selective pentameric ligand-gated ion channel, ELIC.The Journal of general physiology · 2026Article
- Discovery and mechanism of negative allosteric modulation of the α7 nicotinic acetylcholine receptor by nanobodies.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- A new framework for nicotinic receptor-targeted therapeutic strategies in psychiatric and neurodegenerative disorders.Frontiers in cellular neuroscience · 2026Article
- Remimazolam Attenuates Neurological Injury After TBI: A Potential Role of α7nAChR-Associated Mitophagy Enhancement and Pyroptosis Suppression in BV2 Cells.Drug design, development and therapy · 2026Article
- Structure-Function Studies of Pentameric Ligand-Gated Ion Channels: Combining Experimental and Computational Approaches.Advances in experimental medicine and biology · 2026Review
- Characterization of an Open-Channel Structure and Lateral Conduction Pathway in the Cation-Selective Pentameric Ligand-Gated Ion Channel, ELIC.bioRxiv : the preprint server for biology · 2025Article
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Authors and funding
6 authors.
Funding
Abstract
The α7 nicotinic acetylcholine receptor is a pentameric ligand-gated ion channel that plays an important role in neuronal signaling throughout the nervous system. Its implication in neurological disorders and inflammation has spurred the development of numerous compounds that enhance channel activation. However, the therapeutic potential of these compounds has been limited by the characteristically fast desensitization of the α7 receptor. Using recent high-resolution structures from cryo-EM, and all-atom molecular dynamic simulations augmented by Markov state modeling, here we explore the mechanism of α7 receptor desensitization and its implication on allosteric modulation. The results provide a precise characterization of the desensitization gate and illuminate the mechanism of ion-pore opening/closing with an agonist bound. In addition, the simulations reveal the existence of a short-lived, open-channel intermediate between the activated and desensitized states that rationalizes the paradoxical pharmacology of the L247T mutant and may be relevant to type-II allosteric modulation. This analysis provides an interpretation of the signal transduction mechanism and its regulation in α7 receptors.
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