ArticleThe Journal of biological chemistry2017
The Startle Disease Mutation E103K Impairs Activation of Human Homomeric α1 Glycine Receptors by Disrupting an Intersubunit Salt Bridge across the Agonist Binding Site.
Article in The Journal of biological chemistry, 2017. 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, 12 citations in OpenAlex.
- Dynamics and Interplay of the Binding Pockets in the Glycine Receptor.Journal of chemical information and modeling · 2025Article
- Mechanisms underlying modulation of human GlyRα3 by ZnScience advances · 2024Article
- Exploring the Activation Process of the Glycine Receptor.Journal of the American Chemical Society · 2024Article
- State-dependent protein-lipid interactions of a pentameric ligand-gated ion channel in a neuronal membrane.PLoS computational biology · 2021Article
- The startle disease mutation α1S270T predicts shortening of glycinergic synaptic currents.The Journal of physiology · 2020Article
- A Refined Open State of the Glycine Receptor Obtained via Molecular Dynamics Simulations.Structure (London, England : 1993) · 2020Article
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
Abstract
Glycine receptors (GlyR) belong to the pentameric ligand-gated ion channel (pLGIC) superfamily and mediate fast inhibitory transmission in the vertebrate CNS. Disruption of glycinergic transmission by inherited mutations produces startle disease in man. Many startle mutations are in GlyRs and provide useful clues to the function of the channel domains. E103K is one of few startle mutations found in the extracellular agonist binding site of the channel, in loop A of the principal side of the subunit interface. Homology modeling shows that the side chain of Glu-103 is close to that of Arg-131, in loop E of the complementary side of the binding site, and may form a salt bridge at the back of the binding site, constraining its size. We investigated this hypothesis in recombinant human α1 GlyR by site-directed mutagenesis and functional measurements of agonist efficacy and potency by whole cell patch clamp and single channel recording. Despite its position near the binding site, E103K causes hyperekplexia by impairing the efficacy of glycine, its ability to gate the channel once bound, which is very high in wild type GlyR. Mutating Glu-103 and Arg-131 caused various degrees of loss-of-function in the action of glycine, whereas mutations in Arg-131 enhanced the efficacy of the slightly bigger partial agonist sarcosine (
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