ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2012
The α1K276E startle disease mutation reveals multiple intermediate states in the gating of glycine receptors.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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40 citing papers in PubMed, 62 citations in OpenAlex.
- Gating mechanism of the human α1β GlyR by glycine.Structure (London, England : 1993) · 2024Article
- Mapping the molecular motions of 5-HTeLife · 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
- Structure and Mechanism of Glycine Receptor Elucidated by Cryo-Electron Microscopy.Frontiers in pharmacology · 2022Review
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- Orthosteric and Allosteric Activation of Human 5-HTBiophysical journal · 2020Article
- The startle disease mutation α1S270T predicts shortening of glycinergic synaptic currents.The Journal of physiology · 2020Article
- Influence of nonsynaptic α1 glycine receptors on ethanol consumption and place preference.Addiction biology · 2020Article
- A Refined Open State of the Glycine Receptor Obtained via Molecular Dynamics Simulations.Structure (London, England : 1993) · 2020Article
- The mechanism of DNA unwinding by the eukaryotic replicative helicase.Nature communications · 2019Article
- Distinctive single-channel properties of α4β2-nicotinic acetylcholine receptor isoforms.PloS one · 2019Article
- Article
- GABAScientific reports · 2017Article
- The Startle Disease Mutation E103K Impairs Activation of Human Homomeric α1 Glycine Receptors by Disrupting an Intersubunit Salt Bridge across the Agonist Binding Site.The Journal of biological chemistry · 2017Article
- Single-Channel Recording of Ligand-Gated Ion Channels.Cold Spring Harbor protocols · 2016Article
- Bayesian Statistical Inference in Ion-Channel Models with Exact Missed Event Correction.Biophysical journal · 2016Article
- Improved resolution of single channel dwell times reveals mechanisms of binding, priming, and gating in muscle AChR.The Journal of general physiology · 2016Article
- Structural mechanisms of activation and desensitization in neurotransmitter-gated ion channels.Nature structural & molecular biology · 2016Review
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5 authors at 2 institutions in 2 countries.
Funding
Abstract
Loss-of-function mutations in human glycine receptors cause hyperekplexia, a rare inherited disease associated with an exaggerated startle response. We have studied a human disease mutation in the M2-M3 loop of the glycine receptor α1 subunit (K276E) using direct fitting of mechanisms to single-channel recordings with the program HJCFIT. Whole-cell recordings from HEK293 cells showed the mutation reduced the receptor glycine sensitivity. In single-channel recordings, rat homomeric α1 K276E receptors were barely active, even at 200 mM glycine. Coexpression of the β subunit partially rescued channel function. Heteromeric mutant channels opened in brief bursts at 300 μM glycine (a concentration that is near-maximal for wild type) and reached a maximum one-channel open probability of about 45% at 100 mm glycine (compared to 96% for wild type). Distributions of apparent open times contained more than one component in high glycine and, therefore, could not be described by mechanisms with only one fully liganded open state. Fits to the data were much better with mechanisms in which opening can also occur from more than one fully liganded intermediate (e.g., "primed" models). Brief pulses of glycine (∼3 ms, 30 mM) applied to mutant channels in outside-out patches activated currents with a slower rise time (1.5 ms) than those of wild-type channels (0.2 ms) and a much faster decay. These features were predicted reasonably well by the mechanisms obtained from fitting single-channel data. Our results show that, by slowing and impairing channel gating, the K276E mutation facilitates the detection of closed reaction intermediates in the activation pathway of glycine channels.
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