The Sigma-1 receptor is an ER-localized type II membrane protein

Area of Science:

• Cellular Biology
• Neuroscience
• Molecular Biology

Background:

• The Sigma-1 receptor (S1R) is a transmembrane protein crucial for cellular homeostasis and implicated in neuroprotection.
• S1R dysfunction is linked to neurodegenerative diseases like ALS, but its precise cellular localization and topology remain debated.
• Understanding S1R topology is vital for developing effective therapeutic interventions.

Purpose of the Study:

• To definitively determine the topology and plasma membrane localization of the Sigma-1 receptor (S1R).
• To resolve conflicting reports regarding S1R membrane orientation and cellular distribution.
• To assess the impact of S1R agonists and ER stress on its localization.

Main Methods:

• Utilized protease protection assays and N-glycosylation mapping on untagged S1R to determine topology.
• Employed surface fluorescence-activated cell sorting and cell surface biotinylation to assess plasma membrane presence.
• Investigated S1R localization under conditions of S1R agonist treatment and ER stress.

Main Results:

• Unambiguously established S1R as a type II membrane protein with a cytosolic N-terminus.
• Demonstrated significant ER retention of S1R, with negligible presence at the plasma membrane.
• Confirmed ER retention irrespective of S1R agonists or ER stress induction.

Conclusions:

• The Sigma-1 receptor is primarily localized to the endoplasmic reticulum, challenging previous assumptions of plasma membrane presence.
• The established type II membrane topology provides a clearer structural understanding of S1R.
• These findings necessitate a re-evaluation of S1R-targeting therapeutic strategies, focusing on its ER localization.