Wong Adrian Y C, Hristova Elitza, Ahlskog Nina, Tasse Louis-Alexandre, Ngsee Johnny K, Chudalayandi Prakash, Bergeron Richard
Neuroscience, Ottawa Hospital Research Institute, Ottawa (A.Y.C.W., E.H., N.A., L.-A.T., J.K.N, P.C., R.B.), and Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa (J.K.N., R.B.), Ontario, Canada.
Neuroscience, Ottawa Hospital Research Institute, Ottawa (A.Y.C.W., E.H., N.A., L.-A.T., J.K.N, P.C., R.B.), and Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa (J.K.N., R.B.), Ontario, Canada
Mol Pharmacol. 2016 Sep;90(3):238-53. doi: 10.1124/mol.116.104018. Epub 2016 Jul 14.
The sigma-1 receptor (σ-1R) is an endoplasmic reticulum resident chaperone protein involved in a plethora of cellular functions, and whose disruption has been implicated in a wide range of diseases. Genetic analysis has revealed two σ-1R mutants involved in neuromuscular disorders. A point mutation (E102Q) in the ligand-binding domain results in the juvenile form of amyotrophic lateral sclerosis (ALS16), and a 20 amino-acid deletion (Δ31-50) in the putative cytosolic domain leads to a form of distal hereditary motor neuropathy. We investigated the localization and functional properties of these mutants in cell lines using confocal imaging and electrophysiology. The σ-1R mutants exhibited a significant increase in mobility, aberrant localization, and enhanced block of the inwardly rectifying K(+) channel Kir2.1, compared with the wild-type σ-1R. Thus, these σ-1R mutants have different functional properties that could contribute to their disease phenotypes.
σ-1受体（σ-1R）是一种内质网驻留伴侣蛋白，参与多种细胞功能，其功能紊乱与多种疾病有关。基因分析发现了两个与神经肌肉疾病相关的σ-1R突变体。配体结合域中的一个点突变（E102Q）导致青少年型肌萎缩侧索硬化症（ALS16），而假定的胞质域中的20个氨基酸缺失（Δ31-50）导致一种远端遗传性运动神经病。我们使用共聚焦成像和电生理学研究了这些突变体在细胞系中的定位和功能特性。与野生型σ-1R相比，σ-1R突变体的迁移率显著增加，定位异常，并且对内向整流钾通道Kir2.1的阻断增强。因此，这些σ-1R突变体具有不同的功能特性，这可能导致它们的疾病表型。
