The essential roles of protein–protein interaction in sigma-1 receptor functions

σ-1R is the well-known subtype of σ-Rs that were originally proposed in 1976 (Martin et al., 1976). σ-1R is a 223 amino acid integral membrane protein consisting of a short N-terminus, a large C-terminus tail, and two transmembrane domains: one at the N-terminus and the other in the middle of the protein (Su et al., 2010). σ-1Rs are distributed throughout the brain. At the subcellular level, σ-1Rs are mainly localized at the endoplasmic reticulum (ER)/mitochondrial associated membranes (MAM) and at very low levels in post-synaptic thickenings of the neuron (Alonso et al., 2000; Su et al., 2010). σ-1Rs at ER/MAM membranes exist in clustered globular structures that are enriched with cholesterol and neutral lipids (Hayashi and Su, 2003, 2005). Several categories of drugs bind to σ-1Rs, for example: cocaine, dihydroepiandrosterone, dimethyl tryptamine (DMT), psychotomimetic compounds, and haloperidol (antagonist). The steroids and DMT were proposed to act as endogenous ligands for the σ-1R. Studies from various laboratories performed on heterologous, in vivo and ex vivo systems by employing multidisciplinary techniques demonstrated that the σ-1R interacts with numerous cellular components (Su et al., 2010), e.g., different classes of ion channels, kinases, G-protein coupled receptors (GPCRs), etc. The σ-1R associates with voltage-gated ion channels, e.g., Na+, K+, and Ca2+. Interaction of the σ-1R with voltage-gated K+ and Ca2+ channels results in either inhibition or enhancement in the activities of these ion channels, whereas σ-1R interaction with voltagegated Na+ channels results in inhibition of the channel activity (Kourrich et al., 2012). On the other hand, σ-1R enhances the activity of N-methyl-D-aspartate receptors (NMDARs) (a ligand-gated ion channel) and dopamine D1 receptors (a GPCR) (Monnet et al., 1990; Navarro et al., 2010). The σ-1R modulation of D1R is through protein–protein interactions (Navarro et al., 2010). However, it is yet to be determined whether σ-1R modulates the NMDAR function through protein– protein interactions. Nevertheless, a recent study demonstrated that σ-1R inhibits the activity of small conductance Ca2+-activated K+-channels (SK channels), and consequently potentiates the NMDAR function (Martina et al., 2007). It is still unknown if there is any physical association between SK channels and σ-1Rs. How does the σ-1R, being an intracellular protein, modulate the functions of numerous cellular components that are present at the plasma membrane? The prevailing hypothesis is that under resting conditions, at ER/MAM, σ-1Rs are associated with chaperone called BiP. Upon activation of σ-1Rs by their agonists (at concentrations ∼ equal to or less than 10 times their Ki value), σ-1R dissociates from BiP and modulates the function of inositol triphosphate (IP3) receptors. The σ-1R modulation of IP3 receptor function consequently affects Ca2+ influx and signaling into the mitochondria (Hayashi and Su, 2007). However, if σ-1R agonists are present at high concentrations (∼>10 times their Ki value) or during the ER stress, σ-1R dissociates from BiP and translocates to the plasma membrane or plasmalemma and modulates the activities of various cellular components via protein–protein interactions (Su et al., 2010). While this model is promising, several outstanding questions remain to be addressed with respect to σ-1Rs and their association with cellular components, especially different classes of ion channels (Figure 1). For instance, first, it needs to be clarified whether the σ-1R modulates multiple cellular components at the plasma membrane or at the plasmalemma of neurons (Su et al., 2010). Second, it is unclear at the moment if the σ-1R associates with ion channels (e.g., voltage-gated Na+ or K+ channels) at the ER/MAM, and after association, whether or not the entire complex (σ-1R-ion channel) is translocated to the plasma membrane. Third, investigations from different laboratories demonstrated that the treatment of animals with several σ-1R ligands alter the behavior of animals in various behavioral paradigms such as cocaineinduced behavioral response, NMDARantagonism induced amnesia, etc. Hence, it remains to be investigated if there is any link between σ-1Rs association with voltage-gated and/or ligand-gated ion channels, and the alteration in animal behavior, at least in the above-mentioned conditions. Forth, how the σ-1R modulates the functions of voltage-gated and ligand-gated ion channels heterogeneously and to a varying degree remains elusive. Although there can be multiple factors involved, the following reasons could play an important role in differential regulation of voltage-gated and ligand-gated ion channels by σ-1Rs. (a) Recently, it is shown that the σ-1R could exist in dimers (Chu et al., 2013); therefore, do the dimers of σ-1R associate with ion channels? (b) What is the stoichiometry of the σ-1R interaction with ion channels? (c) Several lines of evidence demonstrate that there exist subtypes within the σ-1Rs (Bergeron and Debonnel, 1997; Shioda et al., 2012); thus, do these subtypes display differences in association with ion channels? (d) What is the conformational crystal structure of the σ-1R