Anavex Life Sciences Corp (AVXL)

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The Sigma-1 receptor is an ER-localized type II membrane protein
Neeraj Sharma 1, Chaitanya Patel 1, Marina Shenkman 1, Amit Kessel 2, Nir Ben-Tal 2, Gerardo Z Lederkremer 3

1The Shmunis School of Biomedicine and Cancer Research, Cell Biology Division, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel.
2School of Neurobiology, Biochemistry and Biophysics, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
3The Shmunis School of Biomedicine and Cancer Research, Cell Biology Division, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: [e-mail].
PMID: 34648767 DOI: 10.1016/j.jbc.2021.101299

Abstract
The Sigma-1 receptor (S1R) is a transmembrane protein with important roles in cellular homeostasis in normal physiology and in disease. Especially in neurodegenerative diseases, S1R activation has been shown to provide neuroprotection by modulating calcium signaling, mitochondrial function and reducing endoplasmic reticulum (ER) stress. S1R missense mutations are one of the causes of the neurodegenerative Amyotrophic Lateral Sclerosis and distal hereditary motor neuronopathies. Although the S1R has been studied intensively, basic aspects remain controversial, such as S1R topology and whether it reaches the plasma membrane. To address these questions, we have undertaken several approaches. C-terminal tagging with a small biotin-acceptor peptide and BirA biotinylation in cells suggested a type II membrane orientation (cytosolic N-terminus). However, N-terminal tagging gave an equal probability for both possible orientations. This might explain conflicting reports in the literature, as tags may affect the protein topology. Therefore, we studied untagged S1R using a protease protection assay and a glycosylation mapping approach, introducing N-glycosylation sites. Both methods provided unambiguous results showing that the S1R is a type II membrane protein with a short cytosolic N-terminal tail. Assessments of glycan processing, surface fluorescence-activated cell sorting, and cell surface biotinylation indicated ER-retention, with insignificant exit to the plasma membrane, in the absence or presence of S1R agonists or of ER stress. These findings may have important implications for S1R-based therapeutic approaches.

https://pubmed.ncbi.nlm.nih.gov/34648767/

Blarcamesine and Anavex 3-71 are both sigma 1 receptor agonists.

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