RT Journal Article
SR Electronic
T1 Aberrant Subcellular Dynamics of Sigma-1 Receptor Mutants Underlying Neuromuscular Diseases
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 238
OP 253
DO 10.1124/mol.116.104018
VO 90
IS 3
A1 Adrian Y. C. Wong
A1 Elitza Hristova
A1 Nina Ahlskog
A1 Louis-Alexandre Tasse
A1 Johnny K. Ngsee
A1 Prakash Chudalayandi
A1 Richard Bergeron
YR 2016
UL http://molpharm.aspetjournals.org/content/90/3/238.abstract
AB 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.