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

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 K ir 2.1, compared with the wild-type σ -1R. Thus, these σ -1R mutants have different functional properties that could contribute to their disease phenotypes.