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Review
. 2023 Jan 19;24(3):1971.
doi: 10.3390/ijms24031971.

Overview of Sigma-1R Subcellular Specific Biological Functions and Role in Neuroprotection

Véronik Lachance  1   2 , Sara-Maude Bélanger  1   2 , Célia Hay  1   2 , Victoria Le Corvec  1   2 , Vina Banouvong  1   2 , Mathieu Lapalme  1   2 , Khadija Tarmoun  1   2 , Guillaume Beaucaire  1 , Marc P Lussier  2   3 , Saïd Kourrich  1   2   4
Affiliations
Review

Overview of Sigma-1R Subcellular Specific Biological Functions and Role in Neuroprotection

Véronik Lachance et al. Int J Mol Sci. .

Abstract

For the past several years, fundamental research on Sigma-1R (S1R) protein has unveiled its necessity for maintaining proper cellular homeostasis through modulation of calcium and lipid exchange between the endoplasmic reticulum (ER) and mitochondria, ER-stress response, and many other mechanisms. Most of these processes, such as ER-stress response and autophagy, have been associated with neuroprotective roles. In fact, improving these mechanisms using S1R agonists was beneficial in several brain disorders including neurodegenerative diseases. In this review, we will examine S1R subcellular localization and describe S1R-associated biological activity within these specific compartments, i.e., the Mitochondrion-Associated ER Membrane (MAM), ER-Lipid Droplet (ER-LD) interface, ER-Plasma Membreane (ER-PM) interface, and the Nuclear Envelope (NE). We also discussed how the dysregulation of these pathways contributes to neurodegenerative diseases, while highlighting the cellular mechanisms and key binding partners engaged in these processes.

Keywords: ER stress; Sigma-1R; calcium; chaperone; endoplasmic reticulum; homeostasis; lipid.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Intracellular membrane contact sites known to harbor S1R.
Figure 2
Figure 2
Representation of S1R role in lipid and calcium exchanges observed in lipid raft at the MAM. Left side; agonist-induced activity of S1R promotes its interaction with StAR and supports cholesterol exchange between ER and mitochondria through interaction with VDAC2 and potentially TOM40, which enhances steroidogenesis. Right side: Upon agonist-binding, S1R dissociates from BiP and associates with IP3R3. S1R binding to IP3R3 promotes Ankyrin protein dissociation’s from IP3R3 and supports calcium exchange from the ER to mitochondria. MOM (mitochondria outer membrane).
Figure 3
Figure 3
Summary of autophagy process. (1) Nucleation of the phagophore. (2) Elongation and maturation of the phagophore into an autophagosome. (3) Autophagosome fusion with lysosome. S1R seems to be involved in this step. (4) Formation of the autolysosome. (5) Degradation and recycling of the autolysosome contents.
Figure 4
Figure 4
Scheme of S1R at the ER-LD contact site and its activity in lipid export from the ER and compartmentalization within LDs. S1R-enriched lipid raft at the ER controls lipid compartmentalization and export from the ER to lipid droplets.
Figure 5
Figure 5
Function of S1R at the ER-PM junctions in ER-calcium entry.
Figure 6
Figure 6
Role of S1R at the ER-NE contact site and its role in nucleocytoplasmic transport, stabilization of the NPC, and gene transcription.
See this image and copyright information in PMC

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