ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2013
The GLRA1 missense mutation W170S associates lack of Zn2+ potentiation with human hyperekplexia.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 19 citations in OpenAlex.
- Mechanisms underlying modulation of human GlyRα3 by ZnScience advances · 2024Article
- Methods for negating the impact of zinc contamination to allow characterization of positive allosteric modulators of glycine receptors.Frontiers in molecular neuroscience · 2024Article
- Positive Allosteric Modulators of Glycine Receptors and Their Potential Use in Pain Therapies.Pharmacological reviews · 2022Review
- Advances in hyperekplexia and other startle syndromes.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2021Review
- Excessive Startle with NovelJournal of clinical neurology (Seoul, Korea) · 2020Article
- A Missense Mutation A384P Associated with Human Hyperekplexia Reveals a Desensitization Site of Glycine Receptors.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2018Article
- Impaired Glycine Receptor Trafficking in Neurological Diseases.Frontiers in molecular neuroscience · 2018Review
- Interactions between Zinc and Allosteric Modulators of the Glycine Receptor.The Journal of pharmacology and experimental therapeutics · 2017Article
- The GlyR Extracellular β8-β9 Loop - A Functional Determinant of Agonist Potency.Frontiers in molecular neuroscience · 2017Article
- Luteolin Attenuates Airway Mucus Overproduction via Inhibition of the GABAergic System.Scientific reports · 2016Article
- Investigating the Mechanism by Which Gain-of-function Mutations to the α1 Glycine Receptor Cause Hyperekplexia.The Journal of biological chemistry · 2016Article
- The Free Zinc Concentration in the Synaptic Cleft of Artificial Glycinergic Synapses Rises to At least 1 μM.Frontiers in molecular neuroscience · 2016Article
- Tonic zinc inhibits spontaneous firing in dorsal cochlear nucleus principal neurons by enhancing glycinergic neurotransmission.Neurobiology of disease · 2015Article
- The impact of human hyperekplexia mutations on glycine receptor structure and function.Molecular brain · 2014Review
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Hyperekplexia is a neurological disorder associated primarily with mutations in the α1 subunit of glycine receptors (GlyRs) that lead to dysfunction of glycinergic inhibitory transmission. To date, most of the identified mutations result in disruption of surface expression or altered channel properties of α1-containing GlyRs. Little evidence has emerged to support an involvement of allosteric GlyR modulation in human hyperekplexia. Here, we report that recombinant human GlyRs containing α1 or α1β subunits with a missense mutation in the α1 subunit (W170S), previously identified from familial hyperekplexia, caused remarkably reduced potentiation and enhanced inhibition by Zn(2+). Interestingly, mutant α1(W170S)β GlyRs displayed no significant changes in potency or maximum response to glycine, taurine, or β-alanine. By temporally separating the potentiating and the inhibitory effects of Zn(2+), we found that the enhancement of Zn(2+) inhibition resulted from a loss of Zn(2+)-mediated potentiation. The W170S mutation on the background of H107N, which was previously reported to selectively disrupt Zn(2+) inhibition, showed remarkable attenuation of Zn(2+)-mediated potentiation and thus indicated that W170 is an important residue for the Zn(2+)-mediated GlyR potentiation. Moreover, overexpressing the α1(W170S) subunit in cultured rat neurons confirmed the results from heterologous expression. Together, our results reveal a new zinc potentiation site on α1 GlyRs and a strong link between Zn(2+) modulation and human disease.
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