Sigma-1 Receptor Remodels Endoplasmic Reticulum Membrane

Abstract

Sigma-1 Receptor (S1R) is a single-transmembrane intracellular receptor, primarily residing in the endoplasmic reticulum (ER) membrane. Pharmacological activation of the receptor has been shown to be neuroprotective in a number of brain disorders including Alzheimer's, Huntington's diseases, Amyotrophic lateral sclerosis. It has been proposed that S1R functions as an auxiliary regulatory subunit for various ion channels and receptors, modulating their activity and gating properties. However, the molecular mechanism underlying S1R function in the cell remains unknown. In our study we explored S1R-lipid interactions using a combination of biophysical and biochemical approaches. First, we confirmed that S1R localizes at the specific ER compartment - mitochondria-associated membranes (MAM). Then, we showed that wild-type S1R binds to major raft components such as cholesterol and sphingomyelins. We identified protein motifs responsible for S1R-cholesterol interactions. Intact cholesterol-binding sequence was essential for proper S1R targeting to the MAM regions. Finally, we purified and then reconstructed recombinant S1R in artificial lipid bilayers (supported lipid bilayers and giant unilamellar vesicles). Bilayers of different lipid composition were used to study S1R protein-lipid interactions. We discovered that in the presence of cholesterol S1R forms S1R-enriched microdomains, a function that is modulated by sigma-ligands. We propose that on the molecular level S1R may function as a cholesterol-recruiting protein of the ER. This can explain how S1R can modulate and control numerous physiological pathways and provides a new perspective on ER compartmentalization.