The sigma receptor was originally proposed to be a subtype of the G protein-coupled opioid receptors (Su and Hayashi, 2003). However, a series of later experiments confirmed that the sigma receptor is insensitive to naloxone and GTP (Wilke et al., 1999; Su and Hayashi, 2003). Although the sigma-1 receptor (Sig-1R), a subtype of the sigma receptor, has largely been a mystery since its existence was first proposed in the 1970s, its ligands have demonstrated therapeutic potential in a variety of situations (Su and Hayashi, 2003). At the cellular level, the major action site of Sig-1R is the ER (Su et al., 2010). However, it was recently shown that it is highly enriched in a specialized subcomponent of the ER membrane called the mitochondrial-associated ER membrane (MAM) (Hayashi and Su, 2007). Sig-1R ligands modulate cellular functions, such as ion channel activity, neuronal firing, neuronal differentiation, cancer growth, and cell death/apoptosis, as well as behaviors related to neurological and neuropsychiatric disorders such as substance addiction (e.g., cocaine and methamphetamine abuse), depression, schizophrenia, amyotrophic lateral sclerosis, and Alzheimer’s disease (Mavlyutov et al., 2010, 2013; Su et al., 2010; Maurice and Goguadze, 2017; Nguyen et al., 2017). Uniqueness of Sig-1R ligands lies in their mode of action; in experimental animals, they only exert a therapeutic effect under pathological conditions, particularly ER or mitochondrial stress, and have no effect in normal naïve animals (Hayashi and Su, 2004, 2007; Maurice and Goguadze, 2017; Nguyen et al., 2017). In general, they act to normalize physiological or behavioral functions (Hayashi and Su, 2004). The unique “normalizing” effect of Sig-1R ligands may be partially attributed to Sig-1R’s characteristics as a stress protein and molecular chaperone. In this short review, Sig-1R’s cell biological aspects are discussed, with a particular focus on its role in fundamental ER functions.

Recent studies have ascertained that Sig-1R forms oligomers (e.g., trimers) at the ER membrane, creating a Sig-1R ligand–binding pocket (Chu et al., 2013; Schmidt et al., 2016). A crystallographic study demonstrated that Sig-1R has a single transmembrane domain in the middle of the protein, although other studies have proposed models with two transmembrane domains (Ortega-Roldan et al., 2015; Schmidt et al., 2016; Penke et al., 2018). Although the crystallographic study proposed the C-terminus localizing at the cytoplasmic milieu, a recent study using biologically, and physiologically relevant membranes clearly demonstrated that the Sig-1R possesses a long ER-lumenal domain including the C-terminus (Schmidt et al., 2016; Mavlyutov et al., 2017). By expressing ascorbate peroxidase 2 (i.e., APEX2)-tagged Sig-1R in ND7/23 cells or in dorsal root ganglion neurons, Mavlyutov et al. (2017) demonstrated that (i) N-terminus of the Sig-1R faces the cytosol while the C-terminus faces the ER lumen; (ii) the transmembrane domain exists between amino acids 1–80. The C-terminal hydrophobic domain seems to be involved in forming oligomers (Schmidt et al., 2016). Size exclusion chromatography showed that Sig-1R ligands mediate alterations in Sig-1R oligomerization (Gromek et al., 2014). Meanwhile, FRET studies further support the previous finding that Sig-1R agonists and antagonists tend to cause oligomer dissociation and stabilization, respectively (Mishra et al., 2015; Yano et al., 2018).

An assay screening Sig-1R binding proteins identified BiP, an ER molecular chaperone, as one of the major components of the Sig-1R protein complex (Hayashi and Su, 2007). Solution NMR spectroscopy showed that the C-terminal membrane–tethering domain of Sig-1R interacts with full-length BiP or the nucleotide-binding domain of BiP (Ortega-Roldan et al., 2013). This finding raised the unexpected possibility that Sig-1R regulates chaperone activity at the ER. The interaction between Sig-1R and BiP does not change either protein’s stability, excluding the possibility that Sig-1R is a substrate of the BiP chaperone (Hayashi and Su, 2007). A light-scattering assay provided clear evidence that the purified C-terminus of the Sig-1R polypeptide prevents heat-induced protein aggregation in vitro (Hayashi and Su, 2007), suggesting that Sig-1R possesses an innate biological activity similar to that of molecular chaperones. Interaction between purified BiP and the C-terminus of Sig-1R blocks this activity (Hayashi and Su, 2007). Immunoprecipitation and BRET assays have further examined the physiological role of the heteromeric interaction between Sig-1R and BiP. They revealed that (+)-pentazocine causes Sig-1R and BiP to dissociate, but haloperidol inhibits this dissociation (Hayashi and Su, 2007; Yano et al., 2018). As mentioned above, Sig-1R agonists, such as (+)-pentazocine, induce the dissociation of Sig-1R oligomers, but Sig-1R antagonists, such as haloperidol, stabilize them (Gromek et al., 2014; Mishra et al., 2015; Yano et al., 2018). It is likely that Sig-1R multimerization, which is regulated by Sig-1R ligands, is a key factor promoting Sig-R–BiP interaction.

Taken together, the research results to date clearly indicate Sig-1R is a unique chaperone protein that forms homo-oligomers, and interacts with BiP in its dormant state. Upon binding Sig-1R agonists, which mediate the homo-oligomers’ destabilization, and thus lead to dissociation of BiP from Sig-1R, Sig-1R is activated to exert its innate chaperone activity.

The endoplasmic reticulum is a multifunctional intracellular organelle that serves as an intracellular Ca²⁺ store and a factory of protein and lipid synthesis (Hayashi et al., 2009; Penke et al., 2018). Recent discoveries highlight that the ER also regulates stress response (namely the ER stress response) by transmitting signals derived from unfolded proteins accumulating in the ER (Mori, 2015; Penke et al., 2018). The ER dynamically changes its shape by forming a reticular structure throughout the entire cytoplasm, thus enabling physical connections to other subcellular organelles, such as the plasma membrane and mitochondria (Hayashi et al., 2009; Kerkhofs et al., 2017). As discussed below, Sig-1R appears to be involved in these fundamental ER functions (Figure 1).

Sig-1R unique cell biological characteristics are as follows: (1) it is an ER membrane protein which shares no homology with any other mammalian protein and forms homo-oligomers; (2) it is enriched in a specialized ER subdomain which physically contacts the mitochondria (i.e., the MAM); (3) it is activated when cells face ER or oxidative stress and ameliorates this stress, thereby promoting cellular survival; and (4) Sig-1R oligomerization, which is regulated by ligand binding, is a key factor in its activation and association with BiP. Sig-1R’s subcellular localization gives this small molecule the ability to regulate communication among organelles. Its unique mode of activation, which is triggered under ER stress or ROS accumulation, could be exploited to treat human diseases, especially those caused by misfolding proteins accumulating in the nervous system (i.e., conformational diseases such as Alzheimer’s disease, amyotrophic lateral sclerosis, and Parkinson’s disease).

TH has carried out all processes required for preparation of the manuscript.

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.