Aberrant subcellular dynamics of sigma-1 receptor mutants underlying neuromuscular diseases

Abstract

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.