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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    • "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.
    Journal of Pharmacology and Experimental Therapeutics 06/2015; 354(2). DOI:10.1124/jpet.115.224105 · 3.97 Impact Factor
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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.
    FEBS Letters 01/2015; 589(5). DOI:10.1016/j.febslet.2015.01.033 · 3.17 Impact Factor
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    • "Pharmacological studies, however, did not support this classification and this migrantly defiant and enigmatic 'receptor' was then classified as a phencyclidine (PCP) – like binding site located within the NMDA receptor. Still further work, including more selective ligands, molecular analyses and behavioral studies, led to further distinctions that identified two subtypes along with a unique pharmacology (reviews by Katz et al., 2011; Maurice and Su, 2009; Su et al., 2010). At the present time, the sigma-1 receptor is considered to be a unique ligand-regulated molecular chaperone in the endoplasmic reticulum of cells with broad pharmacological and therapeutic functions. "
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    ABSTRACT: Berend Olivier has had a long-standing interest in the utility of animal models for a wide variety of therapeutic indications. His work has spanned multiple types of models, blending ethological, or species typical and naturalistic behaviors, along with methodologies based on learned behavior. He has consistently done so, from an analytical as well as predictive perspective, and has made multiple contributions while working in both the pharmaceutical industry and within an academic institution. Although focused primarily on psychiatric disorders, Berend has conducted research in the area of pain in humans and in animals, demonstrating an expansive appreciation for the breadth, scope and significance of the science and applications of the discipline of pharmacology to these diverse areas. This review focuses on the use of animal models in pain research from the perspective of the long-standing deficiencies in the development of therapeutics in this area and from a preclinical perspective where the translational weaknesses have been quite problematic. The challenges confronting animal models of pain, however, are not unique to this area of research, as they cut across several therapeutic areas. Despite the deficiencies, failures and concerns, existing animal models of pain continue to be of widespread use and are essential to progress in pain research as well as in other areas. Although not focusing on specific animal models of pain, this article seeks to examine general issues facing the use of these models. It does so by exploring alternative approaches which capture recent developments, which build upon principles and concepts we have learned from Berend's contributions, and which provide the prospect of helping to address the absence of novel therapeutics in this area. Copyright © 2015. Published by Elsevier B.V.
    European Journal of Pharmacology 01/2015; 753. DOI:10.1016/j.ejphar.2014.11.046 · 2.53 Impact Factor
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