Disturbed neuronal ER-Golgi sorting of unassembled glycine receptors suggests altered subcellular processing is a cause of human hyperekplexia

Journal article


Publication Details

Author(s): Schaefer N, Kluck C, Price KL, Meiselbach H, Vornberger N, Schwarzinger S, Hartmann S, Langlhofer G, Schulz S, Schlegel N, Brockmann K, Lynch B, Becker CM, Lummis SCR, Villmann C
Journal: The Journal of Neuroscience
Publisher: Society for Neuroscience
Publication year: 2015
Volume: 35
Journal issue: 1
Pages range: 422-37
ISSN: 1529-2401


Abstract

Recent studies on the pathogenic mechanisms of recessive hyperekplexia indicate disturbances in glycine receptor (GlyR) ?1 biogenesis. Here, we examine the properties of a range of novel glycine receptor mutants identified in human hyperekplexia patients using expression in transfected cell lines and primary neurons. All of the novel mutants localized in the large extracellular domain of the GlyR ?1 have reduced cell surface expression with a high proportion of receptors being retained in the ER, although there is forward trafficking of glycosylated subpopulations into the ER-Golgi intermediate compartment and cis-Golgi compartment. CD spectroscopy revealed that the mutant receptors have proportions of secondary structural elements similar to wild-type receptors. Two mutants in loop B (G160R, T162M) were functional, but none of those in loop D/?2-3 were. One nonfunctional truncated mutant (R316X) could be rescued by coexpression with the lacking C-terminal domain. We conclude that a proportion of GlyR ?1 mutants can be transported to the plasma membrane but do not necessarily form functional ion channels. We suggest that loop D/?2-3 is an important determinant for GlyR trafficking and functionality, whereas alterations to loop B alter agonist potencies, indicating that residues here are critical elements in ligand binding.


FAU Authors / FAU Editors

Becker, Cord-Michael Prof. Dr.
Lehrstuhl für Biochemie und Molekulare Medizin
Hartmann, Stephanie
Lehrstuhl für Physiologie
Meiselbach, Heike
Professur für Bioinformatik


External institutions with authors

Georg-August-Universität Göttingen
Julius-Maximilians-Universität Würzburg
Universität Bayreuth
Universitätsklinikum Jena
Universitätsklinikum Magdeburg A.ö.R.
University of Cambridge


How to cite

APA:
Schaefer, N., Kluck, C., Price, K.L., Meiselbach, H., Vornberger, N., Schwarzinger, S.,... Villmann, C. (2015). Disturbed neuronal ER-Golgi sorting of unassembled glycine receptors suggests altered subcellular processing is a cause of human hyperekplexia. The Journal of Neuroscience, 35(1), 422-37. https://dx.doi.org/10.1523/JNEUROSCI.1509-14.2015

MLA:
Schaefer, Natascha, et al. "Disturbed neuronal ER-Golgi sorting of unassembled glycine receptors suggests altered subcellular processing is a cause of human hyperekplexia." The Journal of Neuroscience 35.1 (2015): 422-37.

BibTeX: 

Last updated on 2018-08-10 at 08:25