Communication between the endoplasmic reticulum (ER) and mitochondrion is important for bioenergetics and cellular survival. The ER supplies Ca(2+) directly to mitochondria via inositol 1,4,5-trisphosphate receptors (IP3Rs) at close contacts between the two organelles referred to as mitochondrion-associated ER membrane (MAM). We found here that the ER protein sigma-1 receptor (Sig-1R), which is implicated in neuroprotection, carcinogenesis, and neuroplasticity, is a Ca(2+)-sensitive and ligand-operated receptor chaperone at MAM. Normally, Sig-1Rs form a complex at MAM with another chaperone, BiP. Upon ER Ca(2+) depletion or via ligand stimulation, Sig-1Rs dissociate from BiP, leading to a prolonged Ca(2+) signaling into mitochondria via IP3Rs. Sig-1Rs can translocate under chronic ER stress. Increasing Sig-1Rs in cells counteracts ER stress response, whereas decreasing them enhances apoptosis. These results reveal that the orchestrated ER chaperone machinery at MAM, by sensing ER Ca(2+) concentrations, regulates ER-mitochondrial interorganellar Ca(2+) signaling and cell survival.

The physical association between the endoplasmic reticulum (ER) and mitochondria, which is known as the mitochondria-associated ER membrane (MAM), has important roles in various cellular ‘housekeeping’ functions including the non-vesicular transports of phospholipids. It has recently become clear that the MAM also enables highly efficient transmission of Ca2+ from the ER to mitochondria to stimulate oxidative metabolism and, conversely, might enable the metabolically energized mitochondria to regulate the ER Ca2+ homeostasis. Recent studies have shed light on molecular chaperones such as calnexin, calreticulin, ERp44, ERp57, grp75 and the sigma-1 receptor at the MAM, which regulate the association between the two organelles. The MAM thus integrates signal transduction with metabolic pathways to regulate the communication and functional interactions between the ER and mitochondrion.

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Originally considered an enigmatic protein, the sigma-1 receptor has recently been identified as a unique ligand-regulated molecular chaperone in the endoplasmic reticulum of cells. This discovery causes us to look back at the many proposed roles of this receptor, even before its molecular function was identified, in many diseases such as methamphetamine or cocaine addiction, amnesia, pain, depression, Alzheimer’s disease, stroke, retinal neuroprotection, HIV infection, and cancer. In this review, we examine the reports that have clearly shown an agonist-antagonist relationship regarding sigma-1 receptors in models of those diseases and also review the relatively known mechanisms of action of sigma-1 receptors in an attempt to spur the speculation of readers on how the sigma-1 receptor at the endoplasmic reticulum might relate to so many diseases. We found that the most prominent action of sigma-1 receptors in biological systems including cell lines, primary cultures, and animals is the regulation and modulation of voltage-regulated and ligand-gated ion channels, including Ca2+-, K+-, Na+, Cl-, and SK channels, and NMDA and IP3 receptors. We found that the final output of the action of sigma-1 receptor agonists is to inhibit all above-mentioned voltage-gated ion channels, while they potentiate ligand-gated channels. The inhibition or potentiation induced by agonists is blocked by sigma-1 receptor antagonists. Other mechanisms of action of sigma-1 receptors, and to some extent those of sigma-2 receptors, were also considered. We conclude that the sigma-1 and sigma-2 receptors represent potential fruitful targets for therapeutic developments in combating many human diseases.

Using a rat model of drug craving, we found that the responsiveness to cocaine cues progressively increases or incubates over the first 60 d of cocaine withdrawal. Here we studied whether alterations in brain-derived neurotrophic factor (BDNF) protein levels within the mesolimbic dopamine system are associated with this incubation phenomenon. BDNF is involved in synaptic plasticity and was found to enhance responding for cues associated with natural rewards. Rats were trained to press a lever to receive intravenous cocaine or oral sucrose for 6 hr/d for 10 d; each earned reward was paired with a tone-light cue. Resumption of lever-pressing behavior was then assessed on days 1, 30, or 90 of reward withdrawal. First, resistance to extinction was assessed during 6 hr in which lever presses were not reinforced and the cue was absent. Second, cue-induced reinstatement was assessed after extinction during 1 hr in which responding led to cue presentations. Other rats were killed without testing on days 1, 30, and 90 of reward withdrawal, and BDNF and nerve growth factor (NGF) protein levels were measured in the ventral tegmental area (VTA), accumbens, and amygdala. Lever pressing during extinction and cue-induced reinstatement tests of cocaine craving progressively increased after cocaine withdrawal. Time-dependent changes also were observed during the tests for sucrose craving, with maximal responding on day 30. BDNF, but not NGF, levels in the VTA, accumbens, and amygdala progressively increased after cocaine, but not sucrose, withdrawal. Time-dependent increases in BDNF levels may lead to synaptic modifications that underlie enhanced responsiveness to cocaine cues after prolonged withdrawal periods.

Specific sigma binding sites have been identified in the mammalian brain and lymphoid tissue. In this study, certain gonadal and adrenal steroids, particularly progesterone, were found to inhibit sigma receptor binding in homogenates of brain and spleen. The findings suggest that steroids are naturally occurring ligands for sigma receptors and raise the possibility that these sites mediate some aspects of steroid-induced mental disturbances and alterations in immune functions.

The brain -1 receptors can bind neurosteroids and psychotropic drugs, including neuroleptics and cocaine and are implicated in schizophrenia, depression, and drug dependence. In this study, we found that -1 receptors specifically target lipid storage sites (lipid droplets) on the endoplasmic reticulum by forming a distinct class of lipid microdomains. Both endogenously expressing -1 receptors and transfected C-terminally enhanced yellow fluorescent protein (EYFP)-tagged -1 receptors (Sig-1R-EYFP) target unique "ring-like" structures associated with endoplasmic reticulum reticular networks in NG108-15 cells. The ring-like structures contain neutral lipids and are enlarged by the oleate treatment, indicating that they are endoplasmic reticulum-associated lipid droplets (ER-LDs).-1 receptors colocalize with caveolin-2, a cholesterol-binding protein in lipid rafts on the ER-LDs, but not with adipocyte differentiation-related protein (ADRP), a cytosolic lipid droplet (c-LD)-specific protein. When the double-arginine ER retention signal on the N terminus of -1 receptors is truncated, -1 receptors no longer exist on ER-LDs, but predominantly target c-LDs, which contain ADRP. -1 receptors on ER-LDs form detergent-resistant raft-like lipid microdomains, the buoyancy of which is different from that of plasma membrane lipid rafts. (ϩ)-Pentazocine causes -1 receptors to disappear from the microdomains. N-Terminally EYFP-tagged -1 receptors (EYFP-Sig-1R) failed to target ER-LDs. EYFP-Sig-1R-transfected cells showed an unrestricted distribution of neutral lipids all over the endoplasmic reticulum network, decreases in c-LDs and cholesterol in plasma membranes, and the bulbous aggregation of endoplasmic reticulum. Thus, -1 receptors are unique endoplasmic reticulum proteins that regulate the compartmentalization of lipids on the endoplasmic reticulum and their export from the endoplasmic reticulum to plasma membrane and c-LDs.

The membrane of the endoplasmic reticulum (ER) of a cell forms contacts directly with mitochondria whereby the contact is referred to as the mitochondrion-associated ER membrane or the MAM. Here we found that the MAM regulates cellular survival via an MAM-residing ER chaperone the sigma-1 receptor (Sig-1R) in that the Sig-1R chaperones the ER stress sensor IRE1 to facilitate inter-organelle signaling for survival. IRE1 is found in this study to be enriched at the MAM in CHO cells. We found that IRE1 is stabilized at the MAM by Sig-1Rs when cells are under ER stress. Sig-1Rs stabilize IRE1 and thus allow for conformationally correct IRE1 to dimerize into the long-lasting, activated endonuclease. The IRE1 at the MAM also responds to reactive oxygen species derived from mitochondria. Therefore, the ER-mitochondrion interface serves as an important subcellular entity in the regulation of cellular survival by enhancing the stress-responding signaling between mitochondria, ER, and nucleus.