ArticleThe Journal of biological chemistry2013
Analysis of hyperekplexia mutations identifies transmembrane domain rearrangements that mediate glycine receptor activation.
Article in The Journal of biological chemistry, 2013. 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, 28 citations in OpenAlex.
- Structural basis for domain coupling in heteromeric glycine receptors revealed by an atypical allosteric agonist.Science advances · 2026Article
- Structural insights into GABANature communications · 2024Article
- Allosteric Cholesterol Site in Glycine Receptors Characterized through Molecular Simulations.The journal of physical chemistry. B · 2024Article
- Illumination of a progressive allosteric mechanism mediating the glycine receptor activation.Nature communications · 2023Article
- Glycine neurotransmission: Its role in development.Frontiers in neuroscience · 2022Review
- Exploring the Conformational Impact of Glycine Receptor TM1-2 Mutations Through Coarse-Grained Analysis and Atomistic Simulations.Frontiers in molecular biosciences · 2022Article
- The general anesthetic etomidate and fenamate mefenamic acid oppositely affect GABAEuropean biophysics journal : EBJ · 2020Article
- The startle disease mutation α1S270T predicts shortening of glycinergic synaptic currents.The Journal of physiology · 2020Article
- A Novel Glycine Receptor Variant with Startle Disease Affects Syndapin I and Glycinergic Inhibition.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2020Article
- The synthetic cannabinoid dehydroxylcannabidiol restores the function of a major GABAThe Journal of biological chemistry · 2020Article
- Impaired Glycine Receptor Trafficking in Neurological Diseases.Frontiers in molecular neuroscience · 2018Review
- GABAScientific reports · 2017Article
- String method solution of the gating pathways for a pentameric ligand-gated ion channel.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Investigating the Mechanism by Which Gain-of-function Mutations to the α1 Glycine Receptor Cause Hyperekplexia.The Journal of biological chemistry · 2016Article
- The Intracellular Loop of the Glycine Receptor: It's not all about the Size.Frontiers in molecular neuroscience · 2016Review
- Allosteric and hyperekplexic mutant phenotypes investigated on an α1 glycine receptor transmembrane structure.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- Correlating structural and energetic changes in glycine receptor activation.The Journal of biological chemistry · 2015Article
- Disturbed neuronal ER-Golgi sorting of unassembled glycine receptors suggests altered subcellular processing is a cause of human hyperekplexia.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2015Article
- Disturbances of Ligand Potency and Enhanced Degradation of the Human Glycine Receptor at Affected Positions G160 and T162 Originally Identified in Patients Suffering from Hyperekplexia.Frontiers in molecular neuroscience · 2015Article
- Identification and functional expression of a glutamate- and avermectin-gated chloride channel from Caligus rogercresseyi, a southern Hemisphere sea louse affecting farmed fish.PLoS pathogens · 2014Article
Corrections and comments
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Authors and funding
2 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Pentameric ligand-gated ion channels (pLGICs) mediate numerous physiological processes and are therapeutic targets for a wide range of clinical indications. Elucidating the structural differences between their closed and open states may help in designing improved drugs that bias receptors toward the desired conformational state. We recently showed that two new hyperekplexia mutations, Q226E and V280M, induced spontaneous activity in α1 glycine receptors. Gln-226, located near the top of transmembrane (TM) 1, is closely apposed to Arg-271 at the top of TM2 in the neighboring subunit. Using mutant cycle analysis, we inferred that Q226E induces activation via an enhanced electrostatic attraction to Arg-271. This would tilt the top of TM2 toward TM1 and hence away from the pore axis to open the channel. We also concluded that the increased side chain volume of V280M, in the TM2-TM3 loop, exerts a steric repulsion against Ile-225 at the top of TM1 in the neighboring subunit. We infer that this steric repulsion would tilt the top of TM3 radially outwards against the stationary TM1 and thus provide space for TM2 to relax away from the pore axis to create an open channel. Because the transmembrane domain movements inferred from this functional analysis are consistent with the structural differences evident in the x-ray atomic structures of closed and open state bacterial pLGICs, we propyose that the model of pLGIC activation as outlined here may be broadly applicable across the eukaryotic pLGIC receptor family.
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