Disruption of a structurally important extracellular element in the glycine receptor leads to decreased synaptic integration and signaling resulting in severe startle disease

Natascha Schaefer; Alexandra Berger; Johannes van Brederode; Fang Zheng; Yan Zhang; Sophie Leacock; Laura Littau; Sibylle Jablonka; Sony Malhotra; Maya Topf; Friederike Winter; Daria Davydova; Joseph W Lynch; Christopher J Paige; Christian Alzheimer; Robert J Harvey; Carmen Villmann

doi:10.1523/JNEUROSCI.0009-17.2017

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Disruption of a structurally important extracellular element in the glycine receptor leads to decreased synaptic integration and signaling resulting in severe startle disease

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Disruption of a structurally important extracellular element in the glycine receptor leads to decreased synaptic integration and signaling resulting in severe startle disease

Natascha Schaefer, Alexandra Berger, Johannes van Brederode, Fang Zheng, Yan Zhang, Sophie Leacock, Laura Littau, Sibylle Jablonka, Sony Malhotra, Maya Topf, …

Journal of Neuroscience, Vol.37(33), pp.7948-7961

2017

DOI: https://doi.org/10.1523/JNEUROSCI.0009-17.2017

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Abstract

glycine receptor

startle disease

β8-β9 loop

hydrogen bond network

fast decay

shaky

Functional impairments or trafficking defects of inhibitory glycine receptors (GlyRs) have been linked to human hyperekplexia/startle disease and autism spectrum disorder. We found that lack of synaptic integration of GlyRs, together with disrupted receptor function is responsible for a lethal startle phenotype in a novel spontaneous mouse mutant shaky, caused by a missense mutation Q177K located in the extracellular β8-β9 loop of the GlyR α1 subunit. Recently, structural data provided evidence that the flexibility of the β8-β9 loop is crucial for conformational transitions during opening and closing of the ion channel and represents a novel allosteric binding site in cys-loop receptors. We identified the underlying neuropathological mechanisms in male and female shaky mice through a combination of protein biochemistry, immunocytochemistry and both in vivo and in vitro electrophysiology. Increased expression of the mutant GlyR α1Q177K subunit in vivo was not sufficient to compensate for a decrease in synaptic integration of α1Q177Kβ GlyRs. The remaining synaptic heteromeric α1Q177Kβ GlyRs had decreased current amplitudes with significantly faster decay times. This functional disruption reveals an important role for the GlyR α1 subunit β8-β9 loop in initiating rearrangements within the extracellular-transmembrane GlyR interface and that this structural element is vital for inhibitory GlyR function, signaling and synaptic clustering.

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Title: Disruption of a structurally important extracellular element in the glycine receptor leads to decreased synaptic integration and signaling resulting in severe startle disease
Authors: Natascha Schaefer (Author) - University of Wurzburg, Germany
Alexandra Berger (Author) - University of Toronto, Canada
Johannes van Brederode (Author) - Friedrich-Alexander-University Erlangen-Nürnberg, Germany
Fang Zheng (Author) - Friedrich-Alexander-University Erlangen-Nürnberg, Germany
Yan Zhang (Author) - University of Queensland
Sophie Leacock (Author) - UCL School of Pharmacy, United Kingdom
Laura Littau (Author) - University of Wurzburg, Germany
Sibylle Jablonka (Author) - University of Wurzburg, Germany
Sony Malhotra (Author) - University of Cambridge, United Kingdom
Maya Topf (Author) - UCL Birkbeck College, United Kingdom
Friederike Winter (Author) - Friedrich-Alexander-University Erlangen-Nürnberg, Germany
Daria Davydova (Author) - University of Wurzburg, Germany
Joseph W Lynch (Author) - University of Queensland
Christopher J Paige (Author) - University of Toronto, Canada
Christian Alzheimer (Author) - Friedrich-Alexander-University Erlangen-Nürnberg, Germany
Robert J Harvey (Author) - UCL School of Pharmacy, United Kingdom
Carmen Villmann (Author) - University of Wurzburg, Germany
Publication details: Journal of Neuroscience, Vol.37(33), pp.7948-7961
Publisher: Society for Neuroscience (SFN)
Date published: 2017
DOI: 10.1523/JNEUROSCI.0009-17.2017
ISSN: 0270-6474
Copyright note: Copyright © 2017 Schaefer et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
Organisation Unit: School of Health; University of the Sunshine Coast, Queensland; School of Health and Sport Sciences - Legacy; Centre for Bioinnovation; School of Health and Behavioural Sciences - Legacy
Language: English
Record Identifier: 99451049802621
Output Type: Journal article

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