scholarly journals Hippocampal Endoplasmic Reticulum Stress: Novel Target in PTSD Pharmacotherapy?

2018 ◽  
Vol 11 (3) ◽  
pp. 1269-1274
Author(s):  
Agung Nova Mahendra ◽  
I Nyoman Adi Jaya Putra
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Functional Impairments ◽  
Sigma 1 Receptor ◽  
Increased Risk ◽  
Sigma 1 ◽  
Agonist And Antagonist ◽  
Antidepressant Use ◽  
Novel Target

Posttraumatic stress disorder (PTSD) is an anxiety disorder that occurred in individual who had experienced severe traumatic stresses. This disorder is accompanied by functional impairments in daily activities, comorbidities (such as depression) and increased risk of suicide. Some studies also demonstrate that PTSD is linked to structural and functional impairment of hippocampus. Hippocampal defect has been found in PTSD model, especially in single-prolonged stress (SPS)-induced animal model, with excessive or prolonged endoplasmic reticulum (ER) stress-induced neuronal apoptosis as a proposed mechanism. Unfortunately, this cellular event has not been studied and validated in humans suffering from PTSD. Two chaperones known as glucose-regulated protein 78 (GRP78) and sigma-1 receptor (Sig1R) have been demonstrated to exhibit central roles in mitigating the effects of severe ER stress on cell survival. Several selective serotonin-reuptake inhibitors (SSRIs), such as fluvoxamine and sertraline, are also found to be an agonist and antagonist of sigma-1 receptor (Sig1R) in animal brain cells, respectively. There is also link between antidepressant use and risk of suicidal ideation. Therefore, the authors propose that hippocampal ER stress may be involved in PTSD pathobiology. Pharmacodynamics of currently available therapeutic agents for PTSD and its comorbidities on hippocampal ER stress should be clearly elucidated to promote therapy optimization and drug development.

scholarly journals Sigma 1 Receptor, Cholesterol and Endoplasmic Reticulum Contact Sites

Contact ◽  
2021 ◽  
Vol 4 ◽  
pp. 251525642110265
Author(s):  
Vladimir Zhemkov ◽  
Jen Liou ◽  
Ilya Bezprozvanny
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Composition ◽  
Sigma 1 Receptor ◽  
Functional Roles ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Sigma 1 ◽  
Membrane Contact ◽  
Organelle Communication ◽  
Cellular Organelles

Recent studies indicated potential importance of membrane contact sites (MCS) between the endoplasmic reticulum (ER) and other cellular organelles. These MCS have unique protein and lipid composition and serve as hubs for inter-organelle communication and signaling. Despite extensive investigation of MCS protein composition and functional roles, little is known about the process of MCS formation. In this perspective, we propose a hypothesis that MCS are formed not as a result of random interactions between membranes of ER and other organelles but on the basis of pre-existing cholesterol-enriched ER microdomains.

scholarly journals Sigma-1 Receptor Promotes Mitochondrial Bioenergetics by Orchestrating ER Ca2+ Leak during Early ER Stress

Metabolites ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 422
Author(s):  
Zhanat Koshenov ◽  
Furkan E. Oflaz ◽  
Martin Hirtl ◽  
Johannes Pilic ◽  
Olaf A. Bachkoenig ◽  
...  
Keyword(s):  
Er Stress ◽  
Energy Demand ◽  
Molecular Mechanisms ◽  
High Energy ◽  
Human Neuroblastoma Cell ◽  
Mitochondrial Bioenergetics ◽  
Dependent Manner ◽  
Human Neuroblastoma ◽  
Sigma 1 Receptor ◽  
Sigma 1

The endoplasmic reticulum (ER) is a complex, multifunctional organelle of eukaryotic cells and responsible for the trafficking and processing of nearly 30% of all human proteins. Any disturbance to these processes can cause ER stress, which initiates an adaptive mechanism called unfolded protein response (UPR) to restore ER functions and homeostasis. Mitochondrial ATP production is necessary to meet the high energy demand of the UPR, while the molecular mechanisms of ER to mitochondria crosstalk under such stress conditions remain mainly enigmatic. Thus, better understanding the regulation of mitochondrial bioenergetics during ER stress is essential to combat many pathologies involving ER stress, the UPR, and mitochondria. This article investigates the role of Sigma-1 Receptor (S1R), an ER chaperone, has in enhancing mitochondrial bioenergetics during early ER stress using human neuroblastoma cell lines. Our results show that inducing ER stress with tunicamycin, a known ER stressor, greatly enhances mitochondrial bioenergetics in a time- and S1R-dependent manner. This is achieved by enhanced ER Ca2+ leak directed towards mitochondria by S1R during the early phase of ER stress. Our data point to the importance of S1R in promoting mitochondrial bioenergetics and maintaining balanced H2O2 metabolism during early ER stress.

At the Crossing of ER Stress and MAMs: A Key Role of Sigma-1 Receptor?

2019 ◽  
pp. 699-718 ◽  
Author(s):  
Benjamin Delprat ◽  
Lucie Crouzier ◽  
Tsung-Ping Su ◽  
Tangui Maurice
Keyword(s):  
Er Stress ◽  
Sigma 1 Receptor ◽  
Sigma 1

The sigma 1 receptor (S1R) is a potential therapeutic target for the treatment of Huntington's disease

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Endoplasmic Reticulum ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Therapeutic Target ◽  
Structural Integrity ◽  
Neuronal Cell ◽  
Glutamate Excitotoxicity ◽  
Potential Therapeutic Target ◽  
Sigma 1 Receptor ◽  
Sigma 1

During the progression of Huntington's disease (HD), changes in Ca2+ signaling cause neuronal cells to lose a range of functional properties. GABAergic medium spiny neurons (MSNs) are able to prevent Ca2+ imbalance in the early stages of the illness through a number of compensatory strategies. However, as people become older, their neuroprotective potential diminishes due to a decrease in metabolic activity and the generation of Ca2+-buffering proteins. Continuing Ca2+ regulation problems exhaust the cells' compensatory abilities, resulting in a continuous surge in cytosolic Ca2+ and neuronal degeneration.The sigma 1 receptor (S1R) is a potential therapeutic target for the treatment of HD because it regulates a number of cytosolic Ca2+-dependent signaling cascades. S1R activation by selective agonists protects neurons from glutamate excitotoxicity, reduces store-operated Ca2+ entry (SOCE) hyperactivation, and maintains the structural integrity of mitochondria-associated endoplasmic reticulum membranes (MAMs), which is required for synchronizing mitochondrial and endoplasmic reticulum (ER) activity to maintain cell bioenergetics balance. Because of the stability of Ca2+ signaling in neurons, pridopidine, a highly selective S1R agonist, has been demonstrated to protect neurons in cellular and animal models of HD.The synaptoprotective effect of pridopidine is very important since it is found in both cortical and striatal neurons, indicating that pridopidine has a systemic influence on HD therapy. Because synaptic dysfunctions are one of the earliest markers of neuropathology at the cellular level, normalization of Ca2+ balance by pridopidine may prevent disease development at the molecular level at the earliest stages. In this regard, the most significant therapeutic advantage of pridopidine will almost certainly be in preventative treatment, even before the start of the first clinical indications, which will improve neuronal cell compensatory abilities and significantly reduce the progression of HD.

scholarly journals Repurposing Sigma-1 Receptor Ligands for COVID-19 Therapy?

2020 ◽  
Vol 11 ◽  
Author(s):  
José Miguel Vela
Keyword(s):  
Stress Response ◽  
Viral Replication ◽  
Er Stress ◽  
Host Cell ◽  
Drug Repurposing ◽  
Host Protein ◽  
Unique Challenge ◽  
Sigma 1 Receptor ◽  
Sigma 1

Outbreaks of emerging infections, such as COVID-19 pandemic especially, confront health professionals with the unique challenge of treating patients. With no time to discover new drugs, repurposing of approved drugs or in clinical development is likely the only solution. Replication of coronaviruses (CoVs) occurs in a modified membranous compartment derived from the endoplasmic reticulum (ER), causes host cell ER stress and activates pathways to facilitate adaptation of the host cell machinery to viral needs. Accordingly, modulation of ER remodeling and ER stress response might be pivotal in elucidating CoV-host interactions and provide a rationale for new therapeutic, host-based antiviral approaches. The sigma-1 receptor (Sig-1R) is a ligand-operated, ER membrane-bound chaperone that acts as an upstream modulator of ER stress and thus a candidate host protein for host-based repurposing approaches to treat COVID-19 patients. Sig-1R ligands are frequently identified in in vitro drug repurposing screens aiming to identify antiviral compounds against CoVs, including severe acute respiratory syndrome CoV-2 (SARS-CoV-2). Sig-1R regulates key mechanisms of the adaptive host cell stress response and takes part in early steps of viral replication. It is enriched in lipid rafts and detergent-resistant ER membranes, where it colocalizes with viral replicase proteins. Indeed, the non-structural SARS-CoV-2 protein Nsp6 interacts with Sig-1R. The activity of Sig-1R ligands against COVID-19 remains to be specifically assessed in clinical trials. This review provides a rationale for targeting Sig-1R as a host-based drug repurposing approach to treat COVID-19 patients. Evidence gained using Sig-1R ligands in unbiased in vitro antiviral drug screens and the potential mechanisms underlying the modulatory effect of Sig-1R on the host cell response are discussed. Targeting Sig-1R is not expected to reduce dramatically established viral replication, but it might interfere with early steps of virus-induced host cell reprogramming, aid to slow down the course of infection, prevent the aggravation of the disease and/or allow a time window to mature a protective immune response. Sig-1R-based medicines could provide benefit not only as early intervention, preventive but also as adjuvant therapy.

Protective effect of a novel sigma-1 receptor agonist is associated with reduced endoplasmic reticulum stress in stroke male mice

2018 ◽  
Vol 96 (10) ◽  
pp. 1707-1716 ◽  
Author(s):  
Ryuta Morihara ◽  
Toru Yamashita ◽  
Xia Liu ◽  
Yumiko Nakano ◽  
Yusuke Fukui ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Protective Effect ◽  
Receptor Agonist ◽  
Male Mice ◽  
Sigma 1 Receptor ◽  
Sigma 1

Sigma 1 receptor stimulation protects against oxidative damage through suppression of the ER stress responses in the human lens

2012 ◽  
Vol 133 (11-12) ◽  
pp. 665-674 ◽  
Author(s):  
Lixin Wang ◽  
Julie A. Eldred ◽  
Peter Sidaway ◽  
Julie Sanderson ◽  
Andrew J.O. Smith ◽  
...  
Keyword(s):  
Oxidative Damage ◽  
Er Stress ◽  
Stress Responses ◽  
Human Lens ◽  
Receptor Stimulation ◽  
Sigma 1 Receptor ◽  
Sigma 1

scholarly journals Sigma-1 Receptor (S1R) Interaction with Cholesterol: Mechanisms of S1R Activation and Its Role in Neurodegenerative Diseases

2021 ◽  
Vol 22 (8) ◽  
pp. 4082
Author(s):  
Vladimir Zhemkov ◽  
Michal Geva ◽  
Michael R. Hayden ◽  
Ilya Bezprozvanny
Keyword(s):  
Endoplasmic Reticulum ◽  
Amino Acid ◽  
Ion Channels ◽  
Effector Proteins ◽  
Trophic Factors ◽  
Signaling Proteins ◽  
Sigma 1 Receptor ◽  
Experimental Systems ◽  
Sigma 1 ◽  
Signaling Receptors

The sigma-1 receptor (S1R) is a 223 amino acid-long transmembrane endoplasmic reticulum (ER) protein. The S1R modulates the activity of multiple effector proteins, but its signaling functions are poorly understood. S1R is associated with cholesterol, and in our recent studies we demonstrated that S1R association with cholesterol induces the formation of S1R clusters. We propose that these S1R-cholesterol interactions enable the formation of cholesterol-enriched microdomains in the ER membrane. We hypothesize that a number of secreted and signaling proteins are recruited and retained in these microdomains. This hypothesis is consistent with the results of an unbiased screen for S1R-interacting partners, which we performed using the engineered ascorbate peroxidase 2 (APEX2) technology. We further propose that S1R agonists enable the disassembly of these cholesterol-enriched microdomains and the release of accumulated proteins such as ion channels, signaling receptors, and trophic factors from the ER. This hypothesis may explain the pleotropic signaling functions of the S1R, consistent with previously observed effects of S1R agonists in various experimental systems.

scholarly journals The role of sigma-1 receptor in organization of endoplasmic reticulum signaling microdomains

2020 ◽  
Author(s):  
Vladimir Zhemkov ◽  
Jonathon A. Ditlev ◽  
Wan-Ru Lee ◽  
Jen Liou ◽  
Michael K. Rosen ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Biological Activity ◽  
Effector Proteins ◽  
Cholesterol Concentration ◽  
Membrane Microdomains ◽  
Binding Motif ◽  
Membrane Thickness ◽  
Sigma 1 Receptor ◽  
Sigma 1

SUMMARYSigma 1 receptor (S1R) is a 223 amino acid-long transmembrane endoplasmic reticulum (ER) protein. S1R modulates activity of multiple effector proteins but its signaling functions are poorly understood. We here test the hypothesis that biological activity of S1R in cells can be explained by its ability to interact with cholesterol and to form cholesterol-enriched microdomains in the ER. Using reduced reconstitution systems, we demonstrate direct effects of cholesterol on S1R clustering. We identify a novel cholesterol-binding motif in the transmembrane region of S1R and demonstrate its importance for S1R clustering. We demonstrate that S1R-induced membrane microdomains have increased local membrane thickness. Increased local cholesterol concentration and membrane thickness in these domains can modulate signaling of inositol-requiring enzyme 1α (IRE1α) in the ER. Further, S1R agonists cause reduction in S1R clusters, suggesting that biological activity of S1R agonists is linked to remodeling of ER membrane microdomains.

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