Abstract: Initially, the Sigma-1 receptor (S1R) was incorrectly categorized as one of the opioid receptors. But it has since become clear that S1R is a non-opioid non-phencyclidine receptor with molecular chaperone activity. S1R is a 223 amino-acid long protein that shares no clear homology with any other known mammalian proteins, its closest homolog being the fungal ERG2 sterol isomerase. Even its pharmacological counterpart, the Sigma-2 receptor that was only recently cloned, is genetically distinct. S1R is more likely considered as an atypical ligand-modulated chaperone protein. S1R is widely expressed in many organs including brain where its function has mainly been explored. In the brain, S1R is found in neurons as well in astrocytes, microglia or oligodendrocytes. While S1R regulates important glial functions like inflammatory response or supply of neurotrophic factors, this perspective article mostly focuses on the various roles of S1R in neurons. At cellular level, S1R resides mainly as a transmembrane protein in the endoplasmic reticulum (ER) and more particularly in the vicinity of mitochondria. At this subdomain, called mitochondrial associated ER-membranes (MAM), S1R regulates calcium exchange between the two organelles through inositol triphosphate receptor type 3 (IP3R type 3). S1R prevents proteosomal degradation of IP3R but also activates its opening for calcium efflux by dissociating IP3R from the scaffolding protein ankyrin G (Su et al., 2016). As a consequence, increased calcium influx in mitochondria boosts production of the nicotinamide adenine dinucleotide cofactor, stimulates the respiratory complex 1 activity and hence increases ATP biosynthesis (Figure 1). MAM are particularly enriched in cholesterol and supply mitochondria with this precursor for steroidogenesis. S1R can promote cholesterol transfer by interaction with steroidogenic acute regulatory protein and voltage dependant anion channel, both facilitating escort of ER-derived cholesterol across the mitochondrial outer membrane (Su et al., 2016) (Figure 1). Moreover, in normal condition, cognate co-chaperone GRP78/Bip is associated to S1R and the ER stress sensor, inositol requiring enzyme 1 (IRE1), keeping them inactive. But when facing stress condition, GRP78/Bip dissociates from S1R and IRE1. Then S1R can stabilize the proper folding of IRE1 and promotes long lasting dimerization and trans-autophosphorylation of IRE1 (Su et al., 2016). This leads to activation of its ribonuclease function and the subsequent expression of the spliced/active transcription factor X-box binding protein 1, which regulates nuclear production of antioxidant proteins and chaperone proteins. On the other hand, over-expression of S1R or binding of S1R by exogenous or putative endogenous agonists can promote its interaction with ion channels, receptors and kinases, and then finely tunes neuronal excitability and plasticity (Su et al., 2016). Among endogenous agonists are neuroactive steroids such as sulfate esters of pregnenolone or dehydroepiandrosterone, the hallucinogenic N,N-dimethyltryptamine and choline. Nevertheless, it is unclear whether 
endogenous agonists have a true physiological role through S1R in vivo. Finally, upon stimulation by cocaine, S1R protein can translocate to the nuclear envelope, where it binds Emerin to regulate gene transcription by recruiting chromatin-remodelling factors (Su et al., 2016).