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

Autor:	Schaefer N; Institute for Clinical Neurobiology, Julius-Maximilians-University of Würzburg, 97078 Würzburg, Germany., Kluck CJ; Institute of Biochemistry, Department of Biochemistry and Molecular Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany., Price KL; Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, United Kingdom., Meiselbach H; Institute of Biochemistry, Bioinformatics Department, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany., Vornberger N; Institute for Clinical Neurobiology, Julius-Maximilians-University of Würzburg, 97078 Würzburg, Germany., Schwarzinger S; Research Center for Bio-Macromolecules and Department of Biopolymers, University Bayreuth, 95447 Bayreuth, Germany., Hartmann S; Institute of Biochemistry, Department of Biochemistry and Molecular Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany., Langlhofer G; Institute for Clinical Neurobiology, Julius-Maximilians-University of Würzburg, 97078 Würzburg, Germany., Schulz S; Center of Human Genetics and., Schlegel N; Department of Neuropediatrics, Jena University Hospital, 07743 Jena, Germany., Brockmann K; Interdisciplinary Pediatric Center for Children with Developmental Disabilities and Severe Chronic Disorders, University Medical Center, Georg August University, 37075 Göttingen, Germany, and., Lynch B; Temple Street Children's University Hospital, Dublin, Dublin1, Ireland., Becker CM; Institute of Biochemistry, Department of Biochemistry and Molecular Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany., Lummis SC; Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, United Kingdom., Villmann C; Institute for Clinical Neurobiology, Julius-Maximilians-University of Würzburg, 97078 Würzburg, Germany, Villmann_C@ukw.de.
Jazyk:	angličtina
Zdroj:	The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2015 Jan 07; Vol. 35 (1), pp. 422-37.
DOI:	10.1523/JNEUROSCI.1509-14.2015
Abstrakt:	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. (Copyright © 2015 the authors 0270-6474/15/350422-16$15.00/0.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu