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

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 (2015)

Publication Type: Journal article

Publication year: 2015

Journal

Publisher: Society for Neuroscience

Book Volume: 35

Pages Range: 422-37

Journal Issue: 1

DOI: 10.1523/JNEUROSCI.1509-14.2015

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.

Authors with CRIS profile

Involved external institutions

Julius-Maximilians-Universität Würzburg Germany (DE) University of Cambridge United Kingdom (GB) Universität Bayreuth Germany (DE) Universitätsklinikum Jena Germany (DE) Georg-August-Universität Göttingen Germany (DE) Universitätsklinikum Magdeburg A.ö.R. Germany (DE)

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://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.

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