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

摘要: Recent studies on the pathogenic mechanisms of recessive hyperekplexia indicate disturbances in glycine receptor (GlyR) α1 biogenesis. Here, we examine properties a range novel mutants identified human patients using expression transfected cell lines and primary neurons. All localized large extracellular domain GlyR have reduced surface with high proportion receptors being retained ER, although there is forward trafficking glycosylated subpopulations into ER-Golgi intermediate compartment cis-Golgi compartment. CD spectroscopy revealed that mutant proportions secondary structural elements similar to wild-type receptors. Two loop B (G160R, T162M) were functional, but none those D/β2–3 were. One nonfunctional truncated (R316X) could be rescued by coexpression lacking C-terminal domain. We conclude can transported plasma membrane do not necessarily form functional ion channels. suggest an important determinant for functionality, whereas alterations alter agonist potencies, indicating residues here are critical ligand binding.