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Disturbed Neuronal ER-Golgi Sorting of Unassembled Glycine Receptors Suggests Altered Subcellular Processing Is a Cause of Human Hyperekplexia

Title data

Schäfer, Natascha ; Kluck, Christoph J. ; Price, Kerry L. ; Meiselbach, Heike ; Vornberger, Nadine ; Schwarzinger, Stephan ; Hartmann, Stephanie ; Langlhofer, Georg ; Schulz, Solveig ; Schlegel, Nadja ; Brockmann, Knut ; Lynch, Bryan ; Becker, Cord-Michael ; Lummis, Sarah C. R. ; Villmann, Carmen:
Disturbed Neuronal ER-Golgi Sorting of Unassembled Glycine Receptors Suggests Altered Subcellular Processing Is a Cause of Human Hyperekplexia.
In: The Journal of Neuroscience. Vol. 35 (January 2015) Issue 1 . - pp. 422-437.
ISSN 1529-2401
DOI: https://doi.org/10.1523/JNEUROSCI.1509-14.2015

Abstract in another language

Recent studies on the pathogenic mechanisms of recessive hyperekplexia indicate disturbances in glycine receptor (GlyR) α1 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 α1 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/β2-3 were. One nonfunctional truncated mutant (R316X) could be rescued by coexpression with the lacking C-terminal domain. We conclude that a proportion of GlyR α1 mutants can be transported to the plasma membrane but do not necessarily form functional ion channels. We suggest that loop D/β2-3 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.

Further data

Item Type: Article in a journal
Refereed: Yes
Institutions of the University: Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Former Professors > Chair Biopolymers - Univ.-Prof. Dr. Paul Rösch
Result of work at the UBT: Yes
DDC Subjects: 500 Science > 540 Chemistry
500 Science > 570 Life sciences, biology
Date Deposited: 30 Jan 2019 11:02
Last Modified: 30 Jan 2019 11:02
URI: https://eref.uni-bayreuth.de/id/eprint/47134