The sigma-1 receptor (Sig-1R) is an endoplasmic reticulum (ER) protein resides specifically at the interface between ER and mitochondria, called the MAM, where the Sig-1R is recently reported to be involved in certain CNS diseases. In addition to being able to translocate to the plasma membrane to interact with ion channels and other receptors, the Sig-1R is found to exist at the nuclear envelope where it recruits chromatin-remodeling factors to affect the transcription of genes. As well, thorough experimental and bioinformatic means, Sig-1Rs are reported to interact with other membranous or soluble proteins at other loci, including the cytosol. We propose that the Sig-1R is a pluripotent modulator with resultant multiple functional manifestations in the living system.

Introduction Current conventional therapeutic drugs for the treatment of psychiatric or neurodegenerative disorders have certain limitations of use. Psychotherapeutic drugs such as typical and atypical antipsychotics, tricyclic antidepressants, and selective monoamine reuptake inhibitors, aim to normalize the hyper- or hypo-neurotransmission of monoaminergic systems. Despite their great contribution to the outcomes of psychiatric patients, these agents often exert severe side effects and require chronic treatments to promote amelioration of symptoms. Furthermore, drugs available for the treatment of neurodegenerative disorders are severely limited. Areas covered This review discusses recent evidence that has shed light on sigma-1 receptor ligands, which may serve as a new class of antidepressants or neuroprotective agents. Sigma-1 receptors are novel ligand-operated molecular chaperones regulating a variety of signal transduction, ER stress, cellular redox, cellular survival, and synaptogenesis. Selective sigma-1 receptor ligands exert rapid antidepressant-like, anxiolytic, antinociceptive and robust neuroprotective actions in preclinical studies. The review also looks at recent studies which suggest that reactive oxygen species might play a crucial role as signal integrators at the downstream of Sig-1Rs Expert opinion The significant advances in sigma receptor research in the last decade have begun to elucidate the intracellular signal cascades upstream and downstream of sigma-1 receptors. The novel ligand-operated properties of the sigma-1 receptor chaperone may enable a variety of interventions by which stress-related cellular systems are pharmacologically controlled.

Sigma-1 receptors (Sig-1Rs) are endoplasmic reticulum (ER)-resident proteins known to be involved in learning and memory. Dendritic spines in hippocampal neurons play important roles in neuroplasticity and learning and memory. This study tested the hypothesis that Sig-1Rs might regulate denritic spine formation in hippocampal neurons and examined potential mechanisms therein. In rat hippocampal primary neurons, the knockdown of Sig-1Rs by siRNAs causes a deficit in the formation of dendritic spines that is unrelated to ER Ca 2؉ signaling or apoptosis, but correlates with the mitochondrial permeability transition and cytochrome c release, followed by caspase-3 activation, Tiam1 cleavage, and a reduction in Rac1⅐GTP. Sig-1R-knockdown neurons contain higher levels of free radicals when compared to control neurons. The activation of superoxide dismutase or the application of the hydroxyl-free radical scavenger N-acetyl cysteine (NAC) to the Sig-1R-knockdown neurons rescues dendritic spines and mitochondria from the deficits caused by Sig-1R siRNA. Further, the caspase-3-resistant TIAM1 construct C1199DN, a stable guanine exchange factor able to constitutively activate Rac1 in the form of Rac1⅐GTP, also reverses the siRNA-induced dendritic spine deficits. In addition, constitutively active Rac1⅐GTP reverses this deficit. These results implicate Sig-1Rs as endogenous regulators of hippopcampal dendritic spine formation and suggest a free radicalsensitive ER-mitochondrion-Rac1⅐GTP pathway in the regulation of dendritic spine formation in the hippocampus. mitochondria ͉ ROS ͉ N-acetyl cyteine ͉ learning and memory ͉ caspase-3 D endritic spines in the CNS are important for many functions. Dendritic atrophy in the neocortical region is related to aging-induced amnesia, and its reversal improves memory retention (1). Similarly, the loss of dendritic spine-related synapses is currently a strong pathologic correlate of cognitive decline, and synaptic dysfunction is evident long before synapses and neurons are lost (2). On the other hand, exposure to drugs of abuse including cocaine, nicotine, or morphine produces persistent changes, usually in the form of increased dendritic spines and arborizations, in cells in brain regions involved in incentive motivation and reward (3). These persistent changes are thought to represent the neuronal reorganization that contributes to some of the persistent sequelae associated with drug use, including the establishment of motivational conditioning and learning (3).The morphology of dendritic spines and axons is determined by the dynamic cytoskeleton protein actin. Rho family small GTPases including Rho, Cdc42, and Rac1 regulate the dynamics of actin and are critical for neuronal polarization and morphogenesis (4-6). Rho proteins are regulated by guanine nucleotide exchange factors (GEFs). In early stages of neural morphogenesis, the activation of Cdc42 promotes the formation of filopodia, the long thin protrusions serving as primary precursors of axons and dendritic spines (7). However, Ra...

Chaperones are proteins that assist the correct folding of other protein clients either when the clients are being synthesized or at their functional localities. Chaperones are responsible for certain diseases. The sigma-1 receptor is recently identified as a receptor chaperone whose activity can be activated/deactivated by specific ligands. Under physiological conditions, the sigma-1 receptor chaperones the functional IP3 receptor at the endoplasmic reticulum and mitochondrion interface to ensure proper Ca2+ signaling from endoplasmic reticulum into mitochondrion. However, under pathological conditions whereby cells encounter enormous stress that results in the endoplasmic reticulum losing its global Ca2+ homeostasis, the sigma-1 receptor translocates and counteracts the arising apoptosis. Thus, the sigma-1 receptor is a receptor chaperone essential for the metabotropic receptor signaling and for the survival against cellular stress. The sigma-1 receptor has been implicated in many diseases including addiction, pain, depression, stroke, and cancer. Whether the chaperone activity of the sigma-1 receptor attributes to those diseases awaits further investigation.

Dysregulation of cyclin-dependent kinase 5 (cdk5) per relative concentrations of its activators p35 and p25 is implicated in neurodegenerative diseases. P35 has a short t ½ and undergoes rapid proteasomal degradation in its membrane-bound myristoylated form. P35 is converted by calpain to p25, which, along with an extended t ½ , promotes aberrant activation of cdk5 and causes abnormal hyperphosphorylation of tau, thus leading to the formation of neurofibrillary tangles. The sigma-1 receptor (Sig-1R) is an endoplasmic reticulum chaperone that is implicated in neuronal survival. However, the specific role of the Sig-1R in neurodegeneration is unclear. Here we found that Sig-1Rs regulate proper tau phosphorylation and axon extension by promoting p35 turnover through the receptor's interaction with myristic acid. In Sig-1R-KO neurons, a greater accumulation of p35 is seen, which results from neither elevated transcription of p35 nor disrupted calpain activity, but rather to the slower degradation of p35. In contrast, Sig-1R overexpression causes a decrease of p35. Sig-1R-KO neurons exhibit shorter axons with lower densities. Myristic acid is found here to bind Sig-1R as an agonist that causes the dissociation of Sig-1R from its cognate partner binding immunoglobulin protein. Remarkably, treatment of Sig-1R-KO neurons with exogenous myristic acid mitigates p35 accumulation, diminishes tau phosphorylation, and restores axon elongation. Our results define the involvement of Sig-1Rs in neurodegeneration and provide a mechanistic explanation that Sig-1Rs help maintain proper tau phosphorylation by potentially carrying and providing myristic acid to p35 for enhanced p35 degradation to circumvent the formation of overreactive cdk5/p25.A xons are structurally and functionally distinct protrusions of neurons that modulate neurotransmitter release and neural function. Malfunction of axonal maintenance, regeneration, and target recognition contribute to CNS disorders such as Alzheimer's disease (AD), Parkinson's disease, stroke, and spinal cord injuries (1-3). Cyclin-dependent kinase (Cdk) 5 activities within the axon play a significant role in the cytoskeletal dynamics of microtubules and actin neurofilaments (NFs), which determine axonal path and length. Specifically, cdk5 active complexes phosphorylate proteins that contribute to the stabilization or destabilization of microtubules, formation of neurofibrillary tangles, and axonal pathfinding (4-6).Cdk5 is a ubiquitously expressed enzyme; however, its activator, p35, is almost exclusively expressed in neurons (7,8). Cdk5 signaling supports neurite projection and proper neuronal migration (9-11). Dysregulation of cdk5 activity leads to hyperphosphorylation of several substrates, including NF proteins and tau, which causes the formation of neurofibrillary tangles (6, 12). Although the kinetics of cdk5 activity when in complex with p35 or p25 are the same, cdk5/p25 complexes are proposed to be responsible for neurodegenerative pathophysiology because of their longer duration o...

-1 Receptors are endoplasmic reticulum (ER) chaperones that are implicated in the neuroplasticity associated with psychostimulant abuse. We immunocytochemically examined the distribution of -1 receptors in the brain of drug-naive rats and then examined the dynamics of -1 receptors and other ER chaperones in specific brain subregions of rats that self-administered methamphetamine, received methamphetamine passively, or received only saline injections. -1 Receptors were found to be expressed in moderate to high levels in the olfactory bulb, striatum, nucleus accumbens shell, olfactory tubercle, amygdala, hippocampus, red nucleus, ventral tegmental area, substantia nigra, and locus ceruleus. Methamphetamine, whether self-administered or passively received, significantly elevated ER chaperones including the -1 receptor, BiP, and calreticulin in the ventral tegmental area and substantia nigra. In the olfactory bulb, however, only the -1 receptor chaperone was increased, and this increase occurred only in rats that actively self-administered methamphetamine. Consistent with an increase in -1 receptors, extracellular signal-regulated kinase was found to be activated and protein kinase A attenuated in the olfactory bulb of methamphetamine self-administering rats. -1 Receptors in the olfactory bulb were found to be colocalized with dopamine D1 receptors. These results indicate that methamphetamine induces ER stress in the ventral tegmental area and substantia nigra in rats whether the drug is received actively or passively. However, the changes seen only in rats that actively self-administered methamphetamine suggest that D1 and -1 receptors in the olfactory bulb might play an important role in the motivational conditioning/learning aspects of methamphetamine self-administration in the rat.

BackgroundPrenatal exposure of the developing brain to cocaine causes morphological and behavioral abnormalities. Recent studies indicate that cocaine-induced proliferation inhibition and/or apoptosis in neural progenitor cells may play a pivotal role in causing these abnormalities. To understand the molecular mechanism through which cocaine inhibits cell proliferation in neural progenitors, we sought to identify the molecules that are responsible for mediating the effect of cocaine on cell cycle regulation.Methods and FindingsMicroarray analysis followed by quantitative real-time reverse transcription PCR was used to screen cocaine-responsive and cell cycle-related genes in a neural progenitor cell line where cocaine exposure caused a robust anti-proliferative effect by interfering with the G1-to-S transition. Cyclin A2, among genes related to the G1-to-S cell cycle transition, was most strongly down-regulated by cocaine. Down-regulation of cyclin A was also found in cocaine-treated human primary neural and A2B5+ progenitor cells, as well as in rat fetal brains exposed to cocaine in utero. Reversing cyclin A down-regulation by gene transfer counteracted the proliferation inhibition caused by cocaine. Further, we found that cocaine-induced accumulation of reactive oxygen species, which involves N-oxidation of cocaine via cytochrome P450, promotes cyclin A down-regulation by causing an endoplasmic reticulum (ER) stress response, as indicated by increased phosphorylation of eIF2α and expression of ATF4. In the developing rat brain, the P450 inhibitor cimetidine counteracted cocaine-induced inhibition of neural progenitor cell proliferation as well as down-regulation of cyclin A.ConclusionsOur results demonstrate that down-regulation of cyclin A underlies cocaine-induced proliferation inhibition in neural progenitors. The down-regulation of cyclin A is initiated by N-oxidative metabolism of cocaine and consequent ER stress. Inhibition of cocaine N-oxidative metabolism by P450 inhibitors may provide a preventive strategy for counteracting the adverse effects of cocaine on fetal brain development.

The sigma-1 receptor (Sig-1R) is a chaperone that resides mainly at the mitochondrion-associated endoplasmic reticulum (ER) membrane (called the MAMs) and acts as a dynamic pluripotent modulator in living systems. At the MAM, the Sig-1R is known to play a role in regulating the Ca2+ signaling between ER and mitochondria and in maintaining the structural integrity of the MAM. The MAM serves as bridges between ER and mitochondria regulating multiple functions such as Ca2+ transfer, energy exchange, lipid synthesis and transports, and protein folding that are pivotal to cell survival and defense. Recently, emerging evidences indicate that the MAM is critical in maintaining neuronal homeostasis. Thus, given the specific localization of the Sig-1R at the MAM, we highlight and propose that the direct or indirect regulations of the Sig-1R on mitochondrial functions may relate to neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS). In addition, the promising use of Sig-1R ligands to rescue mitochondrial dysfunction-induced neurodegeneration is addressed.