The pharmacology of sigma-1 receptors

Team II Endogenous Neuroprotection in Neurodegenerative Diseases, INSERM U. 710, 34095 Montpellier Cedex 5, France.
Pharmacology [?] Therapeutics (Impact Factor: 9.72). 08/2009; 124(2):195-206. DOI: 10.1016/j.pharmthera.2009.07.001
Source: PubMed


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 Ca(2+)-, 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.

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    • "Sig-1Rs have been shown to translocate to other parts of the cell [10] [11] where they can bind to various ion channels, receptors and kinases, resulting in the modulation of multiple neurotransmitter systems such as glutamate , acetylcholine, and dopamine [12] [13] [14] [15] [16] [17]. The existence of an endogenous ligand for Sig-1R is still under debate, although certain neurosteroids and the trace amine N,N-dimethyltryptamine have been proposed [18]. Sig-1Rs are predominantly expressed in the central nervous system, in particular in limbic regions and brainstem nuclei [19] [20]. "
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    ABSTRACT: Rationale: The Sigma-1 receptor (Sig-1R) is a chaperone protein that has been implicated in drug abuse and addiction. Multiple studies have characterized the role the Sig-1R plays in psychostimulants addiction, but fewer studies have specifically investigated its role in alcohol addiction. We have previously shown that antagonism of the Sig-1R reduces excessive drinking and motivation to drink, whereas agonism induces binge-like drinking in rodents. Objectives: The objectives of these studies were to investigate the impact of Sig-1R gene deletion in C57Bl/6J mice on ethanol drinking and other ethanol-related behaviors. Methods: We used an extensive panel of behavioral tests to examine ethanol actions in male, adult mice lacking Oprs1, the gene encoding the Sig-1R. To compare ethanol drinking behavior, Sig-1 knockout (KO) and wild type (WT) mice were subject to a two-bottle choice, continuous access paradigm with different concentrations of ethanol (3%-20% v/v) vs. water. Consumption of sweet and bitter solutions was also assessed in Sig-1R KO and WT mice. Finally, motor stimulant sensitivity, taste aversion and ataxic effects of ethanol were assessed. Results: Sig-1R KO mice displayed higher ethanol intake compared to WT mice; the two genotypes did not differ in their sweet or bitter taste perception. Sig-1R KO mice showed lower sensitivity to ethanol stimulant effects, but greater sensitivity to its taste aversive effects. Ethanol-induced sedation was unaltered in the mutants. Conclusions: Our results suggest that the deletion of the Sig-1R increases ethanol consumption, likely by decreasing its rewarding effects, and therefore indicating that the Sig-1R is involved in modulation of the reinforcing effects of alcohol.
    Full-text · Article · Oct 2015 · Behavioural brain research
    • "Both subtypes are found in the central nervous system and in peripheral tissues throughout the body. The sigma-1 receptor has been well characterized and functions as a ligand-regulated chaperone protein that modulates the function of other receptors, ion channels, and transporters, and plays a role in the promotion of cell survival (Hayashi and Su, 2007; Maurice and Su, 2009). The sigma-2 receptor is highly expressed in a variety of cancer cell lines (Vilner et al., 1995b) and becomes even more highly upregulated when cancer cells are in a state of rapid proliferation (Mach et al., 1997; Al-Nabulsi et al., 1999; Wheeler et al., 2000). "
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    ABSTRACT: Sigma-2 receptors are promising therapeutic targets due to significant upregulation in tumor cells compared to normal tissue. Here we characterize CM572 (3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)-6-isothiocyanatobenzo[d]oxazol-2(3H)-one) (sigma-1 Ki ≥10 µM, sigma-2 Ki=14.6±6.9 nM), a novel isothiocyanate derivative of the putative sigma-2 antagonist, SN79 (6-acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one). CM572 binds irreversibly to sigma-2 receptors by virtue of the isothiocyanate moiety, but not to sigma-1. Studies in human SK-N-SH neuroblastoma cells revealed that CM572 induced an immediate, dose-dependent rise in cytosolic calcium concentration. A 24 h treatment of SK-N-SH cells with CM572 induced dose-dependent cell death, with an EC50 =7.6±1.7 µM. This effect was sustained over 24 h even after a 60 min pretreatment with CM572, followed by extensive washing to remove ligand, indicating an irreversible effect consistent with the irreversible binding data. Western blot analysis revealed that CM572 also induced cleavage activation of pro-apoptotic Bid. These data suggest irreversible agonist-like activity. Low concentrations of CM572 that were minimally effective were able to significantly attenuate the calcium signal and cell death induced by the sigma-2 agonist CB-64D ((+)-1R,5R-(E)-8-benzylidene-5-(3-hydroxyphenyl)-2-methylmorphan-7-one). CM572 was also cytotoxic against PANC-1 pancreatic and MCF-7 breast cancer cell lines. The cytotoxic activity of CM572 was selective for cancer cells over normal cells, being much less potent against primary human melanocytes and human mammary epithelial cells. Taken together, these data show that CM572 is a selective, irreversible sigma-2 receptor partial agonist. This novel irreversible ligand may further our understanding of the endogenous role of this receptor, in addition to having potential use in targeted cancer diagnosis and therapy. The American Society for Pharmacology and Experimental Therapeutics.
    No preview · Article · Jun 2015 · Journal of Pharmacology and Experimental Therapeutics
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    • "S1R has also been shown to interact with acid-sensing ion channels [9], glutamate receptors [10], and dopamine receptors [11]. S1R is highly expressed in the central nervous system (CNS), primarily in the cerebral cortex, hippocampus and cerebellar Purkinje cells [12] [13], and binds a large number of small molecules (opiates, antipsychotics, antidepressants , antihistamines, phencyclidine-like compounds, b-adrenergic receptor ligands, cocaine, dimethyltryptamine, progesterone, and sphingosine), many of which have been shown to modulate the effect of S1R on receptors and ion channels (reviewed in [14] [15]). Thus, S1R is a potential therapeutic target in the treatment of a range of diseases of the CNS, including schizophrenia, Alzheimer's and Parkinson's diseases, amnesia, depression, amyotrophic lateral sclerosis and addiction. "
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    ABSTRACT: The sigma-1 receptor (S1R) is a ligand-regulated membrane chaperone protein associated with endoplasmic reticulum stress response, and modulation of ion channel activities at the plasma membrane. We report here a solution NMR study of a S1R construct (S1R(Δ35)) in which only the first transmembrane domain and the eight-residue N-terminus have been removed. The second transmembrane helix is found to be composed of residues 91-107, which corresponds to the first steroid binding domain-like region. The cytosolic domain is found to contain three helices, and the secondary structure and backbone dynamics of the chaperone domain are consistent with that determined previously for the chaperone domain alone. The position of TM2 provides a framework for ongoing studies of S1R ligand binding and oligomerisation.
    Full-text · Article · Jan 2015 · FEBS Letters
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