Aberrant Subcellular Dynamics of Sigma-1 Receptor Mutants Underlying Neuromuscular Diseases

• Published in: Molecular pharmacology 2016-09, Vol.90 (3), p.238-253
• Main Authors: Wong, Adrian Y.C., Hristova, Elitza, Ahlskog, Nina, Tasse, Louis-Alexandre, Ngsee, Johnny K., Chudalayandi, Prakash, Bergeron, Richard
• Format: Article
• Language: English
• Subjects: Animals; CHO Cells; Cricetinae; Cricetulus; Fibroblasts - metabolism; Fluorescence Recovery After Photobleaching; Mice, Inbred C57BL; Models, Biological; Mutant Proteins - metabolism; Neuromuscular Diseases - metabolism; Receptors, sigma - metabolism; Recombinant Fusion Proteins - metabolism; Shab Potassium Channels - metabolism; Sigma-1 Receptor; Subcellular Fractions - metabolism; Transfection
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.116.104018

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.