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The Intriguing Sigma-1 and Sigma-2 Receptors and Their Potential Therapeutic Roles 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (15 February 2023) | Viewed by 32451

Special Issue Editors

INSERM UMR-S1198, University of Montpellier, CEDEX 5, 34095 Montpellier, France
Interests: sigma-1 receptor; neuroprotection; neurodegenerative diseases; Alzheimer; butyrylcholinesterase; learning and memory; brain plasticity; animal behavior
Special Issues, Collections and Topics in MDPI journals
Department of Pharmacy-Drug Sciences, University of Bari “A. Moro”, Via Orabona 4, 70125 Bari, Italy
Interests: receptor; protein; drug design
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Almost five decades after their discovery, the role of sigma receptors in health and disease is still an intriguing subject. The sigma-1 subtype has been defined as a pluripotent chaperone that interacts with several client proteins. Its recently obtained crystal structure, which shows a peculiar folding, will facilitate the understanding of the oligomerization/polymerization processes that address the sigma-1 receptor functions. Drugs interacting with the sigma-1 subtype have potential for the treatment of CNS disfunctions, neurodegenerative diseases, pain, cocaine abuse, and tumors. After diverse hypotheses, the sigma-2 subtype was recently identified as TMEM97, rejuvenating interest in sigma-2-related research. The overexpression of this subtype in tumor tissues and its role in cell proliferation have mostly driven the research in the oncology field, but recent evidence has highlighted sigma-2 as the receptor responsible for the binding of Abeta oligomers to neurons; one sigma-2 ligand is now in clinical trials for the treatment of Alzheimer’s disease. Surprisingly, sigma receptors have been identified as host proteins for interaction with SARS-CoV-2 proteins, with one sigma ligand performing 20-fold better than hydroxychloroquine in the antiviral assays.

This Special Issue will collect data from the experts in the sigma receptor field with the aim of disseminating knowledge about these pluripotent proteins and advancing research toward their full understanding and possible therapeutic applications.

Dr. Tangui Maurice
Dr. Carmen Abate
Guest Editors

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Keywords

  • sigma-1 receptor
  • sigma-2 receptor
  • TMEM97
  • cancer
  • neurodegeneration
  • neuroprotection
  • pain
  • SAR
  • SAfiR
  • CNS disorders

Published Papers (16 papers)

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Editorial

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4 pages, 208 KiB  
Editorial
The Intriguing Sigma-1 and Sigma-2 Receptors and Their Potential Therapeutic Roles 2.0
by Carmen Abate and Tangui Maurice
Int. J. Mol. Sci. 2023, 24(21), 15868; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms242115868 - 01 Nov 2023
Viewed by 556
Abstract
For some time now, the research on sigma receptors has been at a high level of maturity but, despite everything that has already been achieved, further work in this field still holds huge appeal, with vast possibilities for original discoveries [...] Full article

Research

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14 pages, 2325 KiB  
Article
Structure-Based Modeling of Sigma 1 Receptor Interactions with Ligands and Cholesterol and Implications for Its Biological Function
by Meewhi Kim and Ilya Bezprozvanny
Int. J. Mol. Sci. 2023, 24(16), 12980; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241612980 - 19 Aug 2023
Viewed by 1114
Abstract
The sigma 1 receptor (S1R) is a 223-amino-acid-long transmembrane endoplasmic reticulum (ER) protein. The S1R plays an important role in neuronal health and it is an established therapeutic target for neurodegenerative and neuropsychiatric disorders. Despite its importance in physiology and disease, the biological [...] Read more.
The sigma 1 receptor (S1R) is a 223-amino-acid-long transmembrane endoplasmic reticulum (ER) protein. The S1R plays an important role in neuronal health and it is an established therapeutic target for neurodegenerative and neuropsychiatric disorders. Despite its importance in physiology and disease, the biological function of S1R is poorly understood. To gain insight into the biological and signaling functions of S1R, we took advantage of recently reported crystal structures of human and Xenopus S1Rs and performed structural modeling of S1R interactions with ligands and cholesterol in the presence of the membrane. By combining bioinformatics analysis of S1R sequence and structural modelling approaches, we proposed a model that suggests that S1R may exist in two distinct conformations—“dynamic monomer” (DM) and “anchored monomer” (AM). We further propose that equilibrium between AM and DM conformations of S1R is essential for its biological function in cells, with AM conformation facilitating the oligomerization of S1R and DM conformation facilitating deoligomerization. Consistent with experimental evidence, our hypothesis predicts that increased levels of membrane cholesterol and S1R antagonists should promote the oligomeric state of S1R, but S1R agonists and pathogenic mutations should promote its deoligomerization. Obtained results provide mechanistic insights into signaling functions of S1R in cells, and the proposed model may help to explain neuroprotective effects of S1R modulators. Full article
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20 pages, 4142 KiB  
Article
BS148 Reduces the Aggressiveness of Metastatic Melanoma via Sigma-2 Receptor Targeting
by Claudia Sorbi, Silvia Belluti, Claudio Giacinto Atene, Federica Marocchi, Pasquale Linciano, Neena Roy, Elia Paradiso, Livio Casarini, Simone Ronsisvalle, Tommaso Zanocco-Marani, Livio Brasili, Luisa Lanfrancone, Carol Imbriano, Giulia Di Rocco and Silvia Franchini
Int. J. Mol. Sci. 2023, 24(11), 9684; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24119684 - 02 Jun 2023
Cited by 1 | Viewed by 1420
Abstract
The management of advanced-stage melanoma is clinically challenging, mainly because of its resistance to the currently available therapies. Therefore, it is important to develop alternative therapeutic strategies. The sigma-2 receptor (S2R) is overexpressed in proliferating tumor cells and represents a promising vulnerability to [...] Read more.
The management of advanced-stage melanoma is clinically challenging, mainly because of its resistance to the currently available therapies. Therefore, it is important to develop alternative therapeutic strategies. The sigma-2 receptor (S2R) is overexpressed in proliferating tumor cells and represents a promising vulnerability to target. Indeed, we have recently identified a potent S2R modulator (BS148) that is effective in melanoma. To elucidate its mechanism of action, we designed and synthesized a BS148 fluorescent probe that enters SK-MEL-2 melanoma cells as assessed using confocal microscopy analysis. We show that S2R knockdown significantly reduces the anti-proliferative effect induced by BS148 administration, indicating the engagement of S2R in BS148-mediated cytotoxicity. Interestingly, BS148 treatment showed similar molecular effects to S2R RNA interference-mediated knockdown. We demonstrate that BS148 administration activates the endoplasmic reticulum stress response through the upregulation of protein kinase R-like ER kinase (PERK), activating transcription factor 4 (ATF4) genes, and C/EBP homologous protein (CHOP). Furthermore, we show that BS148 treatment downregulates genes related to the cholesterol pathway and activates the MAPK signaling pathway. Finally, we translate our results into patient-derived xenograft (PDX) cells, proving that BS148 treatment reduces melanoma cell viability and migration. These results demonstrate that BS148 is able to inhibit metastatic melanoma cell proliferation and migration through its interaction with the S2R and confirm its role as a promising target to treat cancer. Full article
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22 pages, 5408 KiB  
Article
Pharmacological Analysis of GABAA Receptor and Sigma1R Chaperone Interaction: Research Report I―Investigation of the Anxiolytic, Anticonvulsant and Hypnotic Effects of Allosteric GABAA Receptors’ Ligands
by Mikhail V. Voronin, Stanislav V. Shangin, Svetlana A. Litvinova, Elena V. Abramova, Rustam D. Kurbanov, Inna V. Rybina, Yulia V. Vakhitova and Sergei B. Seredenin
Int. J. Mol. Sci. 2023, 24(11), 9580; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24119580 - 31 May 2023
Cited by 1 | Viewed by 1289
Abstract
Two groups of facts have been established in previous drug development studies of the non-benzodiazepine anxiolytic fabomotizole. First, fabomotizole prevents stress-induced decrease in binding ability of the GABAA receptor’s benzodiazepine site. Second, fabomotizole is a Sigma1R chaperone agonist, and exposure to Sigma1R [...] Read more.
Two groups of facts have been established in previous drug development studies of the non-benzodiazepine anxiolytic fabomotizole. First, fabomotizole prevents stress-induced decrease in binding ability of the GABAA receptor’s benzodiazepine site. Second, fabomotizole is a Sigma1R chaperone agonist, and exposure to Sigma1R antagonists blocks its anxiolytic effect. To prove our main hypothesis of Sigma1R involvement in GABAA receptor-dependent pharmacological effects, we performed a series of experiments on BALB/c and ICR mice using Sigma1R ligands to study anxiolytic effects of benzodiazepine tranquilizers diazepam (1 mg/kg i.p.) and phenazepam (0.1 mg/kg i.p.) in the elevated plus maze test, the anticonvulsant effects of diazepam (1 mg/kg i.p.) in the pentylenetetrazole-induced seizure model, and the hypnotic effects of pentobarbital (50 mg/kg i.p.). Sigma1R antagonists BD-1047 (1, 10, and 20 mg/kg i.p.), NE-100 (1 and 3 mg/kg i.p.), and Sigma1R agonist PRE-084 (1, 5, and 20 mg/kg i.p.) were used in the experiments. Sigma1R antagonists have been found to attenuate while Sigma1R agonists can enhance GABAARs-dependent pharmacological effects. Full article
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20 pages, 2443 KiB  
Article
Sigma-2 Receptor Ligand Binding Modulates Association between TSPO and TMEM97
by Bashar M. Thejer, Vittoria Infantino, Anna Santarsiero, Ilaria Pappalardo, Francesca S. Abatematteo, Sarah Teakel, Ashleigh Van Oosterum, Robert H. Mach, Nunzio Denora, Byung Chul Lee, Nicoletta Resta, Rosanna Bagnulo, Mauro Niso, Marialessandra Contino, Bianca Montsch, Petra Heffeter, Carmen Abate and Michael A. Cahill
Int. J. Mol. Sci. 2023, 24(7), 6381; https://doi.org/10.3390/ijms24076381 - 28 Mar 2023
Cited by 4 | Viewed by 1934
Abstract
Sigma-2 receptor (S2R) is a S2R ligand-binding site historically associated with reportedly 21.5 kDa proteins that have been linked to several diseases, such as cancer, Alzheimer’s disease, and schizophrenia. The S2R is highly expressed in various tumors, where it correlates with the proliferative [...] Read more.
Sigma-2 receptor (S2R) is a S2R ligand-binding site historically associated with reportedly 21.5 kDa proteins that have been linked to several diseases, such as cancer, Alzheimer’s disease, and schizophrenia. The S2R is highly expressed in various tumors, where it correlates with the proliferative status of the malignant cells. Recently, S2R was reported to be the transmembrane protein TMEM97. Prior to that, we had been investigating the translocator protein (TSPO) as a potential 21.5 kDa S2R candidate protein with reported heme and sterol associations. Here, we investigate the contributions of TMEM97 and TSPO to S2R activity in MCF7 breast adenocarcinoma and MIA PaCa-2 (MP) pancreatic carcinoma cells. Additionally, the role of the reported S2R-interacting partner PGRMC1 was also elucidated. Proximity ligation assays and co-immunoprecipitation show a functional association between S2R and TSPO. Moreover, a close physical colocalization of TMEM97 and TSPO was found in MP cells. In MCF7 cells, co-immunoprecipitation only occurred with TMEM97 but not with PGRMC1, which was further confirmed by confocal microscopy experiments. Treatment with the TMEM97 ligand 20-(S)-hydroxycholesterol reduced co-immunoprecipitation of both TMEM97 and PGRMC1 in immune pellets of immunoprecipitated TSPO in MP cells. To the best of our knowledge, this is the first suggestion of a (functional) interaction between TSPO and TMEM97 that can be affected by S2R ligands. Full article
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29 pages, 4863 KiB  
Article
Investigation of the Entry Pathway and Molecular Nature of σ1 Receptor Ligands
by Gianmarco Pascarella, Lorenzo Antonelli, Daniele Narzi, Theo Battista, Annarita Fiorillo, Gianni Colotti, Leonardo Guidoni, Veronica Morea and Andrea Ilari
Int. J. Mol. Sci. 2023, 24(7), 6367; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24076367 - 28 Mar 2023
Viewed by 1447
Abstract
The σ1 receptor (σ1-R) is an enigmatic endoplasmic reticulum resident transmembrane protein implicated in a variety of central nervous system disorders and whose agonists have neuroprotective activity. In spite of σ1-R’s physio-pathological and pharmacological importance, two of the most important features required to [...] Read more.
The σ1 receptor (σ1-R) is an enigmatic endoplasmic reticulum resident transmembrane protein implicated in a variety of central nervous system disorders and whose agonists have neuroprotective activity. In spite of σ1-R’s physio-pathological and pharmacological importance, two of the most important features required to fully understand σ1-R function, namely the receptor endogenous ligand(s) and the molecular mechanism of ligand access to the binding site, have not yet been unequivocally determined. In this work, we performed molecular dynamics (MD) simulations to help clarify the potential route of access of ligand(s) to the σ1-R binding site, on which discordant results had been reported in the literature. Further, we combined computational and experimental procedures (i.e., virtual screening (VS), electron density map fitting and fluorescence titration experiments) to provide indications about the nature of σ1-R endogenous ligand(s). Our MD simulations on human σ1-R suggested that ligands access the binding site through a cavity that opens on the protein surface in contact with the membrane, in agreement with previous experimental studies on σ1-R from Xenopus laevis. Additionally, steroids were found to be among the preferred σ1-R ligands predicted by VS, and 16,17-didehydroprogesterone was shown by fluorescence titration to bind human σ1-R, with significantly higher affinity than the prototypic σ1-R ligand pridopidine in the same essay. These results support the hypothesis that steroids are among the most important physiological σ1-R ligands. Full article
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21 pages, 4923 KiB  
Article
Sphingoid Bases Regulate the Sigma-1 Receptor—Sphingosine and N,N’-Dimethylsphingosine Are Endogenous Agonists
by Jing Li, Kenneth A. Satyshur, Lian-Wang Guo and Arnold E. Ruoho
Int. J. Mol. Sci. 2023, 24(4), 3103; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24043103 - 04 Feb 2023
Cited by 1 | Viewed by 1398
Abstract
Both bioactive sphingolipids and Sigma-1 receptor (S1R) chaperones occur ubiquitously in mammalian cell membranes. Endogenous compounds that regulate the S1R are important for controlling S1R responses to cellular stress. Herein, we interrogated the S1R in intact Retinal Pigment Epithelial cells (ARPE-19) with the [...] Read more.
Both bioactive sphingolipids and Sigma-1 receptor (S1R) chaperones occur ubiquitously in mammalian cell membranes. Endogenous compounds that regulate the S1R are important for controlling S1R responses to cellular stress. Herein, we interrogated the S1R in intact Retinal Pigment Epithelial cells (ARPE-19) with the bioactive sphingoid base, sphingosine (SPH), or the pain-provoking dimethylated SPH derivative, N,N’-dimethylsphingosine (DMS). As informed by a modified native gel approach, the basal and antagonist (BD-1047)-stabilized S1R oligomers dissociated to protomeric forms in the presence of SPH or DMS (PRE-084 as control). We, thus, posited that SPH and DMS are endogenous S1R agonists. Consistently, in silico docking of SPH and DMS to the S1R protomer showed strong associations with Asp126 and Glu172 in the cupin beta barrel and extensive van der Waals interactions of the C18 alkyl chains with the binding site including residues in helices 4 and 5. Mean docking free energies were 8.73–8.93 kcal/mol for SPH and 8.56–8.15 kcal/mol for DMS, and calculated binding constants were ~40 nM for SPH and ~120 nM for DMS. We hypothesize that SPH, DMS, and similar sphingoid bases access the S1R beta barrel via a membrane bilayer pathway. We further propose that the enzymatic control of ceramide concentrations in intracellular membranes as the primary sources of SPH dictates availability of endogenous SPH and DMS to the S1R and the subsequent control of S1R activity within the same cell and/or in cellular environments. Full article
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26 pages, 2856 KiB  
Article
Safe and Efficient Sigma1 Ligand: A Potential Drug Candidate for Multiple Sclerosis
by Bénédicte Oxombre, Fahima Madouri, Anne-Sophie Journé, Séverine Ravez, Eloise Woitrain, Pascal Odou, Nathalie Duhal, Sandro Ninni, David Montaigne, Nadira Delhem, Patrick Vermersch and Patricia Melnyk
Int. J. Mol. Sci. 2022, 23(19), 11893; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911893 - 06 Oct 2022
Viewed by 1825
Abstract
Multiple Sclerosis (MS) is an autoimmune demyelinating and neurodegenerative disease of the central nervous system (CNS). Current management strategies suppress or modulate immune function, all with consequences and known side effects. They demonstrate a high level of success in limiting new relapses. However, [...] Read more.
Multiple Sclerosis (MS) is an autoimmune demyelinating and neurodegenerative disease of the central nervous system (CNS). Current management strategies suppress or modulate immune function, all with consequences and known side effects. They demonstrate a high level of success in limiting new relapses. However, the neurodegenerative process still affects both grey and white matter in the central nervous system. The sigma1 (S1R) ligand-regulated chaperone is implicated in many biological processes in various CNS-targeted diseases, acting on neural plasticity, myelination and neuroinflammation. Among the proteins involved in MS, S1R has therefore emerged as a promising new target. Standard and robust methods have been adopted to analyze the adsorption, distribution, metabolism, excretion (ADME) properties, safety pharmacology and toxicology of a previously synthetized simple benzamide-derived compound with nanomolar affinity for S1R, high selectivity, no cytotoxicity and good metabolic stability. The compound was also characterized as an agonist based on well-validated assays prior to in vivo investigations. Interestingly, we found that the oral administration of this compound resulted in an overall significant reduction in clinical progression in an MS experimental model. This effect is mediated through S1R action. Our results further suggest the potential use of this compound in the treatment of MS. Full article
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12 pages, 6182 KiB  
Article
Differential Responses to Sigma-1 or Sigma-2 Receptor Ablation in Adiposity, Fat Oxidation, and Sexual Dimorphism
by Jing Li, Elisa Félix-Soriano, Katherine R. Wright, Hongtao Shen, Lisa A. Baer, Kristin I. Stanford and Lian-Wang Guo
Int. J. Mol. Sci. 2022, 23(18), 10846; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231810846 - 16 Sep 2022
Cited by 4 | Viewed by 1950
Abstract
Obesity is increasing at epidemic rates across the US and worldwide, as are its co-morbidities, including type-2 diabetes and cardiovascular disease. Thus, targeted interventions to reduce the prevalence of obesity are of the utmost importance. The sigma-1 receptor (S1R) and sigma-2 receptor (S2R; [...] Read more.
Obesity is increasing at epidemic rates across the US and worldwide, as are its co-morbidities, including type-2 diabetes and cardiovascular disease. Thus, targeted interventions to reduce the prevalence of obesity are of the utmost importance. The sigma-1 receptor (S1R) and sigma-2 receptor (S2R; encoded by Tmem97) belong to the same class of drug-binding sites, yet they are genetically distinct. There are multiple ongoing clinical trials focused on sigma receptors, targeting diseases ranging from Alzheimer’s disease through chronic pain to COVID-19. However, little is known regarding their gene-specific role in obesity. In this study, we measured body composition, used a comprehensive laboratory-animal monitoring system, and determined the glucose and insulin tolerance in mice fed a high-fat diet. Compared to Sigmar1+/+ mice of the same sex, the male and female Sigmar1−/− mice had lower fat mass (17% and 12% lower, respectively), and elevated lean mass (16% and 10% higher, respectively), but S1R ablation had no effect on their metabolism. The male Tmem97−/− mice exhibited 7% lower fat mass, 8% higher lean mass, increased volumes of O2 and CO2, a decreased respiratory exchange ratio indicating elevated fatty-acid oxidation, and improved insulin tolerance, compared to the male Tmem97+/+ mice. There were no changes in any of these parameters in the female Tmem97−/− mice. Together, these data indicate that the S1R ablation in male and female mice or the S2R ablation in male mice protects against diet-induced adiposity, and that S2R ablation, but not S1R deletion, improves insulin tolerance and enhances fatty-acid oxidation in male mice. Further mechanistic investigations may lead to translational strategies to target differential S1R/S2R regulations and sexual dimorphism for precision treatments of obesity. Full article
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13 pages, 12919 KiB  
Article
Exploration of Diazaspiro Cores as Piperazine Bioisosteres in the Development of σ2 Receptor Ligands
by Kuiying Xu, Chia-Ju Hsieh, Ji Youn Lee, Aladdin Riad, Nicholas J. Izzo, Gary Look, Susan Catalano and Robert H. Mach
Int. J. Mol. Sci. 2022, 23(15), 8259; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23158259 - 27 Jul 2022
Cited by 6 | Viewed by 1908
Abstract
A series of σ2R compounds containing benzimidazolone and diazacycloalkane cores was synthesized and evaluated in radioligand binding assays. Replacing the piperazine moiety in a lead compound with diazaspiroalkanes and the fused octahydropyrrolo[3,4-b] pyrrole ring system resulted in a loss in affinity for the [...] Read more.
A series of σ2R compounds containing benzimidazolone and diazacycloalkane cores was synthesized and evaluated in radioligand binding assays. Replacing the piperazine moiety in a lead compound with diazaspiroalkanes and the fused octahydropyrrolo[3,4-b] pyrrole ring system resulted in a loss in affinity for the σ2R. On the other hand, the bridged 2,5-diazabicyclo[2.2.1]heptane, 1,4-diazepine, and a 3-aminoazetidine analog possessed nanomolar affinities for the σ2R. Computational chemistry studies were also conducted with the recently published crystal structure of the σ2R/TMEM97 and revealed that hydrogen bond interactions with ASP29 and π-stacking interactions with TYR150 were largely responsible for the high binding affinity of small molecules to this protein. Full article
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17 pages, 5101 KiB  
Article
EST79232 and EST79376, Two Novel Sigma-1 Receptor Ligands, Exert Neuroprotection on Models of Motoneuron Degeneration
by Núria Gaja-Capdevila, Neus Hernández, Sandra Yeste, Raquel F. Reinoso, Javier Burgueño, Ana Montero, Manuel Merlos, José M. Vela, Mireia Herrando-Grabulosa and Xavier Navarro
Int. J. Mol. Sci. 2022, 23(12), 6737; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23126737 - 16 Jun 2022
Cited by 2 | Viewed by 1744
Abstract
Motor neuron diseases (MNDs) include sporadic and hereditary neurological disorders characterized by progressive degeneration of motor neurons (MNs). Sigma-1 receptor (Sig-1R) is a protein enriched in MNs, and mutations on its gene lead to various types of MND. Previous studies have suggested that [...] Read more.
Motor neuron diseases (MNDs) include sporadic and hereditary neurological disorders characterized by progressive degeneration of motor neurons (MNs). Sigma-1 receptor (Sig-1R) is a protein enriched in MNs, and mutations on its gene lead to various types of MND. Previous studies have suggested that Sig-1R is a target to prevent MN degeneration. In this study, two novel synthesized Sig-1R ligands, coded EST79232 and EST79376, from the same chemical series, with the same scaffold and similar physicochemical properties but opposite functionality on Sig-1R, were evaluated as neuroprotective compounds to prevent MN degeneration. We used an in vitro model of spinal cord organotypic cultures under chronic excitotoxicity and two in vivo models, the spinal nerve injury and the superoxide dismutase 1 (SOD1)G93A mice, to characterize the effects of these Sig-1R ligands on MN survival and modulation of glial reactivity. The antagonist EST79376 preserved MNs in vitro and after spinal nerve injury but was not able to improve MN death in SOD1G93A mice. In contrast, the agonist EST79232 significantly increased MN survival in the three models of MN degeneration evaluated and had a mild beneficial effect on motor function in SOD1G93A mice. In vivo, Sig-1R ligand EST79232 had a more potent effect on preventing MN degeneration than EST79376. These data further support the interest in Sig-1R as a therapeutic target for neurodegeneration. Full article
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13 pages, 2455 KiB  
Article
Examination of the Novel Sigma-1 Receptor Antagonist, SI 1/28, for Antinociceptive and Anti-allodynic Efficacy against Multiple Types of Nociception with Fewer Liabilities of Use
by Lisa L. Wilson, Shainnel O. Eans, Insitar Ramadan-Siraj, Maria N. Modica, Giuseppe Romeo, Sebastiano Intagliata and Jay P. McLaughlin
Int. J. Mol. Sci. 2022, 23(2), 615; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23020615 - 06 Jan 2022
Cited by 3 | Viewed by 2407
Abstract
Neuropathic pain is a significant problem with few effective treatments lacking adverse effects. The sigma-1 receptor (S1R) is a potential therapeutic target for neuropathic pain, as antagonists for this receptor effectively ameliorate pain in both preclinical and clinical studies. The current research examines [...] Read more.
Neuropathic pain is a significant problem with few effective treatments lacking adverse effects. The sigma-1 receptor (S1R) is a potential therapeutic target for neuropathic pain, as antagonists for this receptor effectively ameliorate pain in both preclinical and clinical studies. The current research examines the antinociceptive and anti-allodynic efficacy of SI 1/28, a recently reported benzylpiperazine derivative and analog of the S1R antagonist SI 1/13, that was 423-fold more selective for S1R over the sigma-2 receptor (S2R). In addition, possible liabilities of respiration, sedation, and drug reinforcement caused by SI 1/28 have been evaluated. Inflammatory and chemical nociception, chronic nerve constriction injury (CCI) induced mechanical allodynia, and adverse effects of sedation in a rotarod assay, conditioned place preference (CPP), and changes in breath rate and locomotor activity were assessed after i.p. administration of SI 1/28. Pretreatment with SI 1/28 produced dose-dependent antinociception in the formalin test, with an ED50 (and 95% C.I.) value of 13.2 (7.42–28.3) mg/kg, i.p. Likewise, SI 1/28 produced dose-dependent antinociception against visceral nociception and anti-allodynia against CCI-induced neuropathic pain. SI 1/28 demonstrated no impairment of locomotor activity, conditioned place preference, or respiratory depression. In summary, SI 1/28 proved efficacious in the treatment of acute inflammatory pain and chronic neuropathy without liabilities at therapeutic doses, supporting the development of S1R antagonists as therapeutics for chronic pain. Full article
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Review

Jump to: Editorial, Research, Other

27 pages, 3677 KiB  
Review
Sigma-2 Receptors—From Basic Biology to Therapeutic Target: A Focus on Age-Related Degenerative Diseases
by Britney N. Lizama, Jennifer Kahle, Susan M. Catalano, Anthony O. Caggiano, Michael Grundman and Mary E. Hamby
Int. J. Mol. Sci. 2023, 24(7), 6251; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24076251 - 26 Mar 2023
Cited by 7 | Viewed by 4210
Abstract
There is a large unmet medical need to develop disease-modifying treatment options for individuals with age-related degenerative diseases of the central nervous system. The sigma-2 receptor (S2R), encoded by TMEM97, is expressed in brain and retinal cells, and regulates cell functions via [...] Read more.
There is a large unmet medical need to develop disease-modifying treatment options for individuals with age-related degenerative diseases of the central nervous system. The sigma-2 receptor (S2R), encoded by TMEM97, is expressed in brain and retinal cells, and regulates cell functions via its co-receptor progesterone receptor membrane component 1 (PGRMC1), and through other protein–protein interactions. Studies describing functions of S2R involve the manipulation of expression or pharmacological modulation using exogenous small-molecule ligands. These studies demonstrate that S2R modulates key pathways involved in age-related diseases including autophagy, trafficking, oxidative stress, and amyloid-β and α-synuclein toxicity. Furthermore, S2R modulation can ameliorate functional deficits in cell-based and animal models of disease. This review summarizes the current evidence-based understanding of S2R biology and function, and its potential as a therapeutic target for age-related degenerative diseases of the central nervous system, including Alzheimer’s disease, α-synucleinopathies, and dry age-related macular degeneration. Full article
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17 pages, 4382 KiB  
Review
Overview of Sigma-1R Subcellular Specific Biological Functions and Role in Neuroprotection
by Véronik Lachance, Sara-Maude Bélanger, Célia Hay, Victoria Le Corvec, Vina Banouvong, Mathieu Lapalme, Khadija Tarmoun, Guillaume Beaucaire, Marc P. Lussier and Saïd Kourrich
Int. J. Mol. Sci. 2023, 24(3), 1971; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24031971 - 19 Jan 2023
Cited by 7 | Viewed by 2117
Abstract
For the past several years, fundamental research on Sigma-1R (S1R) protein has unveiled its necessity for maintaining proper cellular homeostasis through modulation of calcium and lipid exchange between the endoplasmic reticulum (ER) and mitochondria, ER-stress response, and many other mechanisms. Most of these [...] Read more.
For the past several years, fundamental research on Sigma-1R (S1R) protein has unveiled its necessity for maintaining proper cellular homeostasis through modulation of calcium and lipid exchange between the endoplasmic reticulum (ER) and mitochondria, ER-stress response, and many other mechanisms. Most of these processes, such as ER-stress response and autophagy, have been associated with neuroprotective roles. In fact, improving these mechanisms using S1R agonists was beneficial in several brain disorders including neurodegenerative diseases. In this review, we will examine S1R subcellular localization and describe S1R-associated biological activity within these specific compartments, i.e., the Mitochondrion-Associated ER Membrane (MAM), ER–Lipid Droplet (ER–LD) interface, ER–Plasma Membreane (ER–PM) interface, and the Nuclear Envelope (NE). We also discussed how the dysregulation of these pathways contributes to neurodegenerative diseases, while highlighting the cellular mechanisms and key binding partners engaged in these processes. Full article
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48 pages, 5061 KiB  
Review
Chaperone-Dependent Mechanisms as a Pharmacological Target for Neuroprotection
by Mikhail V. Voronin, Elena V. Abramova, Ekaterina R. Verbovaya, Yulia V. Vakhitova and Sergei B. Seredenin
Int. J. Mol. Sci. 2023, 24(1), 823; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24010823 - 03 Jan 2023
Cited by 8 | Viewed by 3628
Abstract
Modern pharmacotherapy of neurodegenerative diseases is predominantly symptomatic and does not allow vicious circles causing disease development to break. Protein misfolding is considered the most important pathogenetic factor of neurodegenerative diseases. Physiological mechanisms related to the function of chaperones, which contribute to the [...] Read more.
Modern pharmacotherapy of neurodegenerative diseases is predominantly symptomatic and does not allow vicious circles causing disease development to break. Protein misfolding is considered the most important pathogenetic factor of neurodegenerative diseases. Physiological mechanisms related to the function of chaperones, which contribute to the restoration of native conformation of functionally important proteins, evolved evolutionarily. These mechanisms can be considered promising for pharmacological regulation. Therefore, the aim of this review was to analyze the mechanisms of endoplasmic reticulum stress (ER stress) and unfolded protein response (UPR) in the pathogenesis of neurodegenerative diseases. Data on BiP and Sigma1R chaperones in clinical and experimental studies of Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease are presented. The possibility of neuroprotective effect dependent on Sigma1R ligand activation in these diseases is also demonstrated. The interaction between Sigma1R and BiP-associated signaling in the neuroprotection is discussed. The performed analysis suggests the feasibility of pharmacological regulation of chaperone function, possibility of ligand activation of Sigma1R in order to achieve a neuroprotective effect, and the need for further studies of the conjugation of cellular mechanisms controlled by Sigma1R and BiP chaperones. Full article
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10 pages, 1611 KiB  
Perspective
SIGMAR1 Confers Innate Resilience against Neurodegeneration
by Simon Couly, Yuko Yasui and Tsung-Ping Su
Int. J. Mol. Sci. 2023, 24(9), 7767; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24097767 - 24 Apr 2023
Cited by 4 | Viewed by 1477
Abstract
The sigma-1 receptor (SIGMAR1) is one of a kind: a receptor chaperone protein. This 223 amino acid-long protein is enriched at the mitochondria-associated endoplasmic reticulum membrane (MAM), a specialized microdomain of the endoplasmic reticulum that is structurally and functionally connected to the mitochondria. [...] Read more.
The sigma-1 receptor (SIGMAR1) is one of a kind: a receptor chaperone protein. This 223 amino acid-long protein is enriched at the mitochondria-associated endoplasmic reticulum membrane (MAM), a specialized microdomain of the endoplasmic reticulum that is structurally and functionally connected to the mitochondria. As a receptor, SIGMAR1 binds a wide spectrum of ligands. Numerous molecules targeting SIGMAR1 are currently in pre-clinical or clinical development. Interestingly, the range of pathologies covered by these studies is broad, especially with regard to neurodegenerative disorders. Upon activation, SIGMAR1 can translocate and interact with other proteins, mostly at the MAM but also in other organelles, which allows SIGMAR1 to affect many cellular functions. During these interactions, SIGMAR1 exhibits chaperone protein behavior by participating in the folding and stabilization of its partner. In this short communication, we will shed light on how SIGMAR1 confers protection against neurodegeneration to the cells of the nervous system and why this ability makes SIGMAR1 a multifunctional therapeutic prospect. Full article
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