Dear Editor,Deciphering the role of any protein in a cell requires knowledge of the structure,subcellular localization,and the topological orientation of the protein within the relevant cells.The Sigma-1 receptor (S1R) largely localized to the endoplasmic reticulum (ER) serves as a pluripotent intracellular signaling molecule with diverse roles in the cell including ion channel modulation,stress signaling,and transcriptional regulation (reviewed in Suet al.,2016),however,the basic topology of this protein within a cell remains controversial.