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Arnold E Ruoho - One of the best experts on this subject based on the ideXlab platform.
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apex2 enhanced electron microscopy distinguishes sigma 1 Receptor localization in the nucleoplasmic reticulum
Oncotarget, 2017Co-Authors: Timur A Mavlyutov, Arnold E Ruoho, Miles L Epstein, Huan Yang, Jay Yang, Lianwang GuoAbstract:// Timur A. Mavlyutov 1, * , Huan Yang 1, * , Miles L. Epstein 2 , Arnold E. Ruoho 2 , Jay Yang 3 and Lian-Wang Guo 1, 4, 5, 6 1 Department of Surgery, Wisconsin Institute for Medical Research, University of Wisconsin, Madison, WI 53705, USA 2 Department of Neuroscience, University of Wisconsin, Madison, WI 53706, USA 3 Department of Anesthesiology, Wisconsin Institute for Medical Research, University of Wisconsin, Madison, WI 53705, USA 4 McPherson Eye Research Institute, University of Wisconsin, Madison, WI 53705, USA 5 Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA 6 Department of Physiology and Cell Biology, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA * These authors contributed equally to this work Correspondence to: Lian-Wang Guo, email: Lianwang.Guo@osumc.edu Keywords: the Sigma-1 Receptor, APEX2-enhanced electron microscopy, nucleoplasmic reticulum, nuclear envelope, serial sectioning Abbreviations: Sig1R-Sigma-1 Receptor, ER-endoplasmic reticulum, NR-nucleoplasmic reticulum, NE-nuclear envelope, EM-electron microscopy Received: March 02, 2017 Accepted: May 04, 2017 Published: May 16, 2017 ABSTRACT The Sigma-1 Receptor (Sig1R) is an endoplasmic reticulum chaperonin that is attracting tremendous interest as a potential anti-neurodegenerative target. While this membrane protein is known to reside in the inner nuclear envelope (NE) and influences transcription, apparent Sig1R presence in the nucleoplasm is often observed, seemingly contradicting its NE localization. We addressed this confounding issue by applying an antibody-free approach of electron microscopy (EM) to define Sig1R nuclear localization. We expressed APEX2 peroxidase fused to Sig1R-GFP in a Sig1R-null NSC34 neuronal cell line generated with CRISPR-Cas9. APEX2-catalyzed gold/silver precipitation markedly improved EM clarity and confirmed an apparent intra-nuclear presence of Sig1R. However, serial sectioning combined with APEX2-enhanced EM revealed that Sig1R actually resided in the nucleoplasmic reticulum (NR), a specialized nuclear compartment formed via NE invagination into the nucleoplasm. NR cross-sections also indicated Sig1R in ring-shaped NR membranes. Thus, this study distinguishes Sig1R in the NR which could otherwise appear localized in the nucleoplasm if detected with low-resolution methods. Our finding is important for uncovering potential Sig1R regulations in the nucleus.
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biochemical pharmacology of the sigma 1 Receptor
Molecular Pharmacology, 2016Co-Authors: Uyen B Chu, Arnold E RuohoAbstract:The Sigma-1 Receptor (S1R) is a 223 amino acid two transmembrane (TM) pass protein. It is a non-ATP-binding nonglycosylated ligand-regulated molecular chaperone of unknown three-dimensional structure. The S1R is resident to eukaryotic mitochondrial-associated endoplasmic reticulum and plasma membranes with broad functions that regulate cellular calcium homeostasis and reduce oxidative stress. Several multitasking functions of the S1R are underwritten by chaperone-mediated direct (and indirect) interactions with ion channels, G-protein coupled Receptors and cell-signaling molecules involved in the regulation of cell growth. The S1R is a promising drug target for the treatment of several neurodegenerative diseases related to cellular stress. In vitro and in vivo functional and molecular characteristics of the S1R and its interactions with endogenous and synthetic small molecules have been discovered by the use of pharmacologic, biochemical, biophysical, and molecular biology approaches. The S1R exists in monomer, dimer, tetramer, hexamer/octamer, and higher oligomeric forms that may be important determinants in defining the pharmacology and mechanism(s) of action of the S1R. A canonical GXXXG in putative TM2 is important for S1R oligomerization. The ligand-binding regions of S1R have been identified and include portions of TM2 and the TM proximal regions of the C terminus. Some client protein chaperone functions and interactions with the cochaperone 78-kDa glucose-regulated protein (binding immunoglobulin protein) involve the C terminus. Based on its biochemical features and mechanisms of chaperone action the possibility that the S1R is a member of the small heat shock protein family is discussed.
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role of the sigma 1 Receptor in amyotrophic lateral sclerosis als
Journal of Pharmacological Sciences, 2015Co-Authors: Timur A Mavlyutov, Miles L Epstein, Lianwang Guo, Arnold E RuohoAbstract:Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease affecting spinal cord motoneurons (MN) with an associative connection to Frontotemporal Lobar Dementia (FTLD). The endoplasmic reticulum (ER) bound Sigma-1 Receptor (S1R) chaperone protein localizes to specialized ER cisternae within 10 nm of the plasma membrane in spinal cord ventral horn cholinergic post synaptic C-terminals. Removal of the S1R gene in the Superoxide Dismutase-1 (SOD-1) mouse model of ALS exacerbated the neurodegenerative condition and resulted in a significantly reduced longevity when compared to the SOD-1/S1R wild type (WT) mouse. The proposed amelioration of the ALS phenotype by the S1R is likely due to a “brake” on excitation of the MN as evidenced by a reduction in action potential generation in the MN of the WT when compared to the S1R KO mouse MN. Although the precise signal transduction pathway(s) regulated by the S1R in the MN has/have not been elucidated at present, it is likely that direct or indirect functional interactions occur between the S1R in the ER cisternae with voltage gated potassium channels and/or with muscarinic M2 Receptor signaling in the post synaptic plasma membrane. Possible mechanisms for regulation of MN excitability by S1R are discussed.
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the oligomeric states of the purified sigma 1 Receptor are stabilized by ligands
Journal of Biological Chemistry, 2014Co-Authors: Katarzyna A Gromek, Arnold E Ruoho, Uyen B Chu, Fabian P Suchy, Hannah R Meddaugh, Russell L Wrobel, Loren M Lapointe, John G Primm, Alessandro Senes, Brian G FoxAbstract:Sigma-1 Receptor (S1R) is a mammalian member of the ERG2 and Sigma-1 Receptor-like protein family (pfam04622). It has been implicated in drug addiction and many human neurological disorders, including Alzheimer and Parkinson diseases and amyotrophic lateral sclerosis. A broad range of synthetic small molecules, including cocaine, (+)-pentazocine, haloperidol, and small endogenous molecules such as N,N-dimethyltryptamine, sphingosine, and steroids, have been identified as regulators of S1R. However, the mechanism of activation of S1R remains obscure. Here, we provide evidence in vitro that S1R has ligand binding activity only in an oligomeric state. The oligomeric state is prone to decay into an apparent monomeric form when exposed to elevated temperature, with loss of ligand binding activity. This decay is suppressed in the presence of the known S1R ligands such as haloperidol, BD-1047, and sphingosine. S1R has a GXXXG motif in its second transmembrane region, and these motifs are often involved in oligomerization of membrane proteins. Disrupting mutations within the GXXXG motif shifted the fraction of the higher oligomeric states toward smaller states and resulted in a significant decrease in specific (+)-[3H]pentazocine binding. Results presented here support the proposal that S1R function may be regulated by its oligomeric state. Possible mechanisms of molecular regulation of interacting protein partners by S1R in the presence of small molecule ligands are discussed.
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lack of sigma 1 Receptor exacerbates als progression in mice
Neuroscience, 2013Co-Authors: Timur A Mavlyutov, Miles L Epstein, Lea Ziskindconhaim, Yakov Verbny, Maria S Huerta, Ismail Zaitoun, Arnold E RuohoAbstract:Abstract The function of the Sigma-1 Receptor (S1R) has been implicated in modulating the activity of various ion channels. In the CNS S1R is enriched in cholinergic postsynaptic densities in spinal cord motoneurons (MNs). Mutations in S1R have been found in familial cases of amyotrophic lateral sclerosis (ALS). In this study we show that a knockout of S1R in the SOD1*G93A mouse model of ALS significantly reduces longevity (end stage). Electrophysiological experiments demonstrate that MN of mice lacking S1R exhibit increased excitability. Taken together the data suggest the S1R acts as a brake on excitability, an effect that might enhance longevity in an ALS mouse model.
Yu Lan - One of the best experts on this subject based on the ideXlab platform.
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novel radioligands for imaging sigma 1 Receptor in brain using positron emission tomography pet
Acta Pharmaceutica Sinica B, 2019Co-Authors: Yu Lan, Ping Bai, Zude Chen, Ramesh Neelamegam, Michael S Placzek, Hao Wang, Stephanie Fiedler, Jing Yang, Gengyang YuanAbstract:The Sigma-1 Receptor (σ1R) is a unique intracellular protein. σ1R plays a major role in various pathological conditions in the central nervous system (CNS), implicated in several neuropsychiatric disorders. Imaging of σ1R in the brain using positron emission tomography (PET) could serve as a noninvasively tool for enhancing the understanding of the disease's pathophysiology. Moreover, σ1R PET tracers can be used for target validation and quantification in diagnosis. Herein, we describe the radiosynthesis, in vivo PET/CT imaging of novel σ1R 11C-labeled radioligands based on 6-hydroxypyridazinone, [11C]HCC0923 and [11C]HCC0929. Two radioligands have high affinities to σ1R, with good selectivity. In mice PET/CT imaging, both radioligands showed appropriate kinetics and distributions. Additionally, the specific interactions of two radioligands were reduced by compounds 13 and 15 (self-blocking). Of the two, [11C]HCC0929 was further investigated in positive ligands blocking studies, using classic σ1R agonist SA 4503 and σ1R antagonist PD 144418. Both σ1R ligands could extensively decreased the uptake of [11C]HCC0929 in mice brain. Besides, the biodistribution of major brain regions and organs of mice were determined in vivo. These studies demonstrated that two radioligands, especially [11C]HCC0929, possessed ideal imaging properties and might be valuable tools for non-invasive quantification of σ1R in brain.
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novel 11c labeled radioligands for imaging sigma 1 Receptor in the brain using positron emission tomography pet
The Journal of Nuclear Medicine, 2019Co-Authors: Yu Lan, Ping Bai, Changning WangAbstract:481 Introduction: The Sigma-1 Receptor is recognized as a unique class of non-G protein coupled, non-ionotropic intracellular chaperone protein within the mitochondria-associated endoplasmic reticulum (ER) membranes [1]. It consists of 223 amino acids with a molecular weight of 25.3 kDa. The X-ray structure of Sigma-1 Receptor showed a membrane-bound trimeric assembly with one transmembrane region [2]. The Sigma-1 Receptor plays a major role in various pathological conditions in the periphery (e.g. vascular diseases, cancer) and in the central nervous system (CNS), where they are implicated in several neuropsychiatric and neurodegenerative disorders including depression, epilepsy, neuropathic pain, Parkinson`s disease (PD) and Alzheimer`s disease (AD) [1, 3]. Imaging of Sigma-1 Receptor in brain using positron emission tomography (PET) could serve as a noninvasively tool for elucidate the distribution and functional roles in vivo and enhance the understanding of the disease`s pathophysiology. Moreover, Sigma-1 Receptor PET tracers can be used for target validation, visualization and quantification of metabolic and biochemical processes as well as diagnosis and prognosis of these CNS diseases [4-6]. Herein, we describe the radiosynthesis, in vivo PET/CT imaging and ex vivo autoradiography of two novel Sigma-1 Receptor radioligands based on pyrimidine scaffold [7], [11C]HCC900424 (1) and [11C]HCC900329 (2). The results showed that these two probes have high specificity, good selectivity and appropriate kinetics and distribution: the brain uptake and wash-out kinetics of [11C]-1 and [11C]-2 in transgenic AD model mouse and health wild-type mice showed significant differences, the concentration of radioligands in AD model mouse is reduced compared to health wild-type mice. Besides, the specific interaction of [11C]-1 and [11C]-2 with Sigma-1 Receptor was reduced by administration of unlabeled 1 and 2 (self-blocking), confirming the selective labeling of Sigma-1 Receptor. In ex vivo radiography of a rat brain reveals high concentration of the radioligand in those regions, which are reported to be in rich of Sigma-1 Receptor. These studies performed with [11C]-1 and [11C]-2 demonstrated that both tracers possess ideal imaging properties as valuable tools for selective non-invasive visualization and quantification of Sigma-1 Receptor in brain, which could accelerate preclinic research and medical develop in Alzheimer`s disease.
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synthesis and biological evaluation of novel sigma 1 Receptor antagonists based on pyrimidine scaffold as agents for treating neuropathic pain
Journal of Medicinal Chemistry, 2014Co-Authors: Yu Lan, Yin Chen, Xudong Cao, Juecheng Zhang, Jie Wang, Yinli Qiu, Tan Zhang, Xin Liu, Bifeng Liu, Guisen ZhangAbstract:The discovery and synthesis of a new series of pyrimidines as potent Sigma-1 Receptor (σ1R) antagonists, associated with pharmacological antineuropathic pain activity, are the focus of this article. The new compounds were evaluated in vitro in σ-1 and σ-2 Receptor binding assays. The nature of the pyrimidine scaffold was crucial for activity, and a basic amine was shown to be necessary according to the known pharmacophoric model. The most promising derivative was 5-chloro-2-(4-chlorophenyl)-4-methyl-6-(3-(piperidin-1-yl)propoxy)pyrimidine (137), which exhibited a high binding affinity to σ1R Receptor (Ki σ1 = 1.06 nM) and good σ-1/2 selectivity (1344-fold). In in vivo tests, compound 137 exerted dose-dependent antinociceptive effects in mice formalin model and rats CCI models of neuropathic pain. In addition, no motor impairments were found in rotarod tests; acceptable pharmacokinetic properties were also noted. These data suggest compound 137 may constitute a novel class of drugs for the treatment of neuropathic pain.
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Synthesis and Biological Evaluation of Novel Sigma‑1 Receptor Antagonists Based on Pyrimidine Scaffold As Agents for Treating Neuropathic Pain
2014Co-Authors: Yu Lan, Yin Chen, Xudong Cao, Juecheng Zhang, Jie Wang, Yinli Qiu, Tan Zhang, Xin Liu, Bifeng LiuAbstract:The discovery and synthesis of a new series of pyrimidines as potent Sigma-1 Receptor (σ1R) antagonists, associated with pharmacological antineuropathic pain activity, are the focus of this article. The new compounds were evaluated in vitro in σ-1 and σ-2 Receptor binding assays. The nature of the pyrimidine scaffold was crucial for activity, and a basic amine was shown to be necessary according to the known pharmacophoric model. The most promising derivative was 5-chloro-2-(4-chlorophenyl)-4-methyl-6-(3-(piperidin-1-yl)propoxy)pyrimidine (137), which exhibited a high binding affinity to σ1R Receptor (Ki σ1 = 1.06 nM) and good σ-1/2 selectivity (1344-fold). In in vivo tests, compound 137 exerted dose-dependent antinociceptive effects in mice formalin model and rats CCI models of neuropathic pain. In addition, no motor impairments were found in rotarod tests; acceptable pharmacokinetic properties were also noted. These data suggest compound 137 may constitute a novel class of drugs for the treatment of neuropathic pain
Teruo Hayashi - One of the best experts on this subject based on the ideXlab platform.
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conversion of psychological stress into cellular stress response roles of the sigma 1 Receptor in the process
Psychiatry and Clinical Neurosciences, 2015Co-Authors: Teruo HayashiAbstract:Psychiatrists empirically recognize that excessive or chronic psychological stress can result in long-lasting impairments of brain functions that partly involve neuronal cell damage. Recent studies begin to elucidate the molecular pathways activated/inhibited by psychological stress. Activation of the hypothalamic–pituitary–adrenal axis under psychological stress causes inflammatory oxidative stresses in the brain, in part due to elevation of cytokines. Psychological stress or neuropathological conditions (e.g., accumulation of β-amyloids) trigger ‘cellular stress responses’, which promote upregulation of molecular chaperones to protect macromolecules from degradation. The unfolded protein response, the endoplasmic reticulum (ER)-specific cellular stress response, has been recently implicated in the pathophysiology of neuropsychiatric disorders and the pharmacology of certain clinically used drugs. The Sigma-1 Receptor is an ER protein whose ligands are shown to exert antidepressant-like and neuroprotective actions. Recent studies found that the Sigma-1 Receptor is a novel ligand-operated ER chaperone that regulates bioenergetics, free radical generation, oxidative stress, unfolded protein response and cytokine signaling. The Sigma-1 Receptor also regulates morphogenesis of neuronal cells, such as neurite outgrowth, synaptogenesis, and myelination, which can be perturbed by cellular stress. The Sigma-1 Receptor may thus contribute to a cellular defense system that protects nervous systems against chronic psychological stress. Findings from sigma Receptor research imply that not only cell surface monoamine effectors but also intracellular molecules, especially those at the ER, may provide novel therapeutic targets for future drug developments.
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sigma 1 Receptor the novel intracellular target of neuropsychotherapeutic drugs
Journal of Pharmacological Sciences, 2015Co-Authors: Teruo HayashiAbstract:Sigma-1 Receptor ligands have been long expected to serve as drugs for treatment of human diseases such as neurodegenerative disorders, depression, idiopathic pain, drug abuse, and cancer. Recent research exploring the molecular function of the Sigma-1 Receptor started unveiling underlying mechanisms of the therapeutic activity of those ligands. Via the molecular chaperone activity, the Sigma-1 Receptor regulates protein folding/degradation, ER/oxidative stress, and cell survival. The chaperone activity is activated or inhibited by synthetic Sigma-1 Receptor ligands in an agonist-antagonist manner. Sigma-1 Receptors are localized at the endoplasmic reticulum (ER) membranes that are physically associated with the mitochondria (MAM: mitochondria-associated ER membrane). In specific types of neurons (e.g., those at the spinal cord), Sigma-1 Receptors are also clustered at ER membranes that juxtapose postsynaptic plasma membranes. Recent studies indicate that Sigma-1 Receptors, partly in sake of its unique subcellular localization, regulate the mitochondria function that involves bioenergetics and free radical generation. The Sigma-1 Receptor may thus provide an intracellular drug target that enables controlling ER stress and free radical generation under pathological conditions.
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Sigma-1 Receptor chaperone at the ER-mitochondrion interface mediates the mitochondrion-ER-nucleus signaling for cellular survival.
PLOS ONE, 2013Co-Authors: Tomohisa Mori, Teruo Hayashi, Eri HayashiAbstract:The membrane of the endoplasmic reticulum (ER) of a cell forms contacts directly with mitochondria whereby the contact is referred to as the mitochondrion-associated ER membrane or the MAM. Here we found that the MAM regulates cellular survival via an MAM-residing ER chaperone the Sigma-1 Receptor (Sig-1R) in that the Sig-1R chaperones the ER stress sensor IRE1 to facilitate inter-organelle signaling for survival. IRE1 is found in this study to be enriched at the MAM in CHO cells. We found that IRE1 is stabilized at the MAM by Sig-1Rs when cells are under ER stress. Sig-1Rs stabilize IRE1 and thus allow for conformationally correct IRE1 to dimerize into the long-lasting, activated endonuclease. The IRE1 at the MAM also responds to reactive oxygen species derived from mitochondria. Therefore, the ER-mitochondrion interface serves as an important subcellular entity in the regulation of cellular survival by enhancing the stress-responding signaling between mitochondria, ER, and nucleus.
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dynamic interaction between sigma 1 Receptor and kv1 2 shapes neuronal and behavioral responses to cocaine
Cell, 2013Co-Authors: Said Kourrich, Teruo Hayashi, Shangyi Tsai, Jian Ying Chuang, Antonello BonciAbstract:SUMMARY The Sigma-1 Receptor (Sig-1R), an endoplasmic reticulum (ER) chaperone protein, is an interorganelle signaling modulator that potentially plays a role in drug-seeking behaviors. However, the brain site of action and underlying cellular mechanisms remain unidentified. We found that cocaine exposure triggers a Sig-1R-dependent upregulation of D-type K + current in the nucleus accumbens (NAc) that results in neuronal hypoactivity and thereby enhances behavioral cocaine response. Combining ex vivo and in vitro studies, we demonstrated that this neuroadaptation is caused by a persistent proteinprotein association between Sig-1Rs and Kv1.2 channels, a phenomenon that is associated to a redistribution of both proteins from intracellular compartments to the plasma membrane. In conclusion, the dynamic Sig-1R-Kv1.2 complex represents a mechanism that shapes neuronal and behavioral response to cocaine. Functional consequences of Sig-1R binding to K + channels may have implications for other chronic diseases where maladaptive intrinsic plasticity and Sig-1Rs are engaged.
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sigma 1 Receptor chaperones regulate the secretion of brain derived neurotrophic factor
Synapse, 2012Co-Authors: Michiko Fujimoto, Teruo Hayashi, Roman Urfer, Shiro MitaAbstract:The Sigma-1 Receptor (Sig-1R) is a novel endoplasmic reticulum (ER) molecular chaperone that regulates protein folding and degradation. The Sig-1R activation by agonists is known to improve memory, promote cell survival, and exert an antidepressant-like action in animals. Cutamesine (SA4503), a selective Sig-1R ligand, was shown to increase BDNF in the hippocampus of rats. How exactly the intracellular chaperone Sig-1R or associated ligand causes the increase of BDNF or any other neurotrophins is unknown. We examined here whether the action of Sig-1Rs may relate to the post-translational processing and release of BDNF in neuroblastoma cell lines. We used in vitro assays and confirmed that cutamesine possesses the bona fide Sig-1R agonist property by causing the dissociation of BiP from Sig-1Rs. The C-terminus of Sig-1Rs exerted robust chaperone activity by completely blocking the aggregation of BDNF and GDNF in vitro. Chronic treatment with cutamesine in rat B104 neuroblastoma caused a time- and dose-dependent potentiation of the secretion of BDNF without affecting the mRNA level of BDNF. Cutamesine decreased the intracellular level of pro-BDNF and mature BDNF whereas increased the extracellular level of mature BDNF. The pulse-chase experiment indicated that the knockdown of Sig-1Rs decreased the secreted mature BDNF in B104 cells without affecting the synthesis of BDNF. Our findings indicate that, in contrast to clinically used antidepressants that promote the transcriptional upregulation of BDNF, the Sig-1R agonist cutamesine potentiates the post-translational processing of neurotrophins. This unique pharmacological profile may provide a novel therapeutic opportunity for the treatment of neuropsychiatric disorders.
Kohji Fukunaga - One of the best experts on this subject based on the ideXlab platform.
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dehydroepiandrosterone administration improves memory deficits following transient brain ischemia through sigma 1 Receptor stimulation
Brain Research, 2015Co-Authors: Yasushi Yabuki, Hisanao Izumi, Norifumi Shioda, Yasuharu Shinoda, Tatuya Ikuno, Kohji FukunagaAbstract:Abstract Dehydroepiandrosterone (DHEA) is the most abundant neurosteroid synthesized de novo in the central nervous system. Oral DHEA administration elicits neuroprotection and cognitive improvement, but mechanisms underlying these functions in cerebral ischemia have remained unclear. Since DHEA is the endogenous ligand for the Sigma-1 Receptor (σ1R), we determined whether oral DHEA administration prevents neuronal cell death and improves cognition via σ1R stimulation in brain ischemia using a 20-min bilateral common carotid artery occlusion (BCCAO) mouse model. Twenty-four hours after BCCAO ischemia, mice were administered DHEA (15 or 30 mg/kg p.o.) daily for 11 consecutive days. Memory deficits following brain ischemia were improved by DHEA administration dose-dependently. Accordingly, DHEA administration significantly prevented neuronal cell death in the hippocampal CA1 region in BCCAO mice. Interestingly, DHEA administration rescued decreases in Ca2+/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation and phosphorylation of extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) in the CA1 region. Moreover, DHEA administration significantly ameliorated decreases in adenosine 5ʹ-triphosphate (ATP) levels and decreased σ1R expression levels in CA1 following BCCAO ischemia. Finally, co-treatment of mice with the σ1R antagonist NE-100 (1 mg/kg, p.o.) blocked DHEA effects on memory improvement and neuroprotection in ischemic mice. Taken together, DHEA prevents neuronal cell death and activates CaMKII via σ1R stimulation, thereby improving cognitive deficits following brain ischemia.
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crucial interactions between selective serotonin uptake inhibitors and sigma 1 Receptor in heart failure
Journal of Pharmacological Sciences, 2013Co-Authors: Md Shenuarin Bhuiyan, Hideaki Tagashira, Kohji FukunagaAbstract:Abstract Depression is associated with a substantial increase in the risk of developing heart failure and is independently associated with increased cardiovascular morbidity and mortality. Inversely, cardiovascular disease can lead to severe depression. Thus, therapy with selective serotonin reuptake inhibitors (SSRIs) is strongly recommended to reduce cardiovascular disease-induced morbidity and mortality. However, molecular mechanisms to support evidence-based SSRI treatment of cardiovascular disease have not been elucidated. We recently found very high expression of the Sigma-1 Receptor, an orphan Receptor, in rat heart tissue and defined the cardiac Sigma-1 Receptor as a direct SSRI target in eliciting cardioprotection in both pressure overload (PO)-induced and transverse aortic constriction (TAC)-induced myocardial hypertrophy models in rodents. Our findings suggest that SSRIs such as fluvoxamine protect against PO- and TAC-induced cardiac dysfunction by upregulating Sigma-1 Receptor expression and stimulating Sigma-1 Receptor–mediated Akt-eNOS signaling. Here, we discuss the association of depression and cardiovascular diseases, the protective mechanism of SSRIs in heart failure patients, and the pathophysiological relevance of Sigma-1 Receptors to progression of heart failure. These findings should promote development of clinical therapeutics targeting the Sigma-1 Receptor in cardiovascular diseases.
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targeting sigma 1 Receptor signaling by endogenous ligands for cardioprotection
Expert Opinion on Therapeutic Targets, 2011Co-Authors: Md Shenuarin Bhuiyan, Kohji FukunagaAbstract:Introduction: The sigma Receptors, initially described as a subtype of opioid Receptors, are now considered to be a unique Receptor expressed in neonatal rat cardiomyocytes and in the plasma membrane of adult rat cardiomyocytes. A number of sigma Receptor ligands influence cardiovascular function and the heart has binding sites for sigma Receptor ligands that alter contractility both in vivo and in vitro. The human Sigma-1 Receptor gene contains a steroid-binding component and gonadal steroid dehydroepiandrosterone (DHEA) which interacts with the Sigma-1 Receptor. Areas covered: We recently documented that the pathophysiological role of the Sigma-1 Receptor in the heart and its modulation using DHEA, was cardioprotective. Moreover, agonist-induced activation of the Sigma-1 Receptor modulates diverse ion channels and thereby regulates heart function. Novel concepts for understanding the pathophysiological relevance of Sigma-1 Receptors in the progression of heart failure, and developing clinical therapeuti...
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targeting sigma 1 Receptor with fluvoxamine ameliorates pressure overload induced hypertrophy and dysfunctions
Expert Opinion on Therapeutic Targets, 2010Co-Authors: Md Shenuarin Bhuiyan, Hideaki Tagashira, Norifumi Shioda, Kohji FukunagaAbstract:Objective: We here investigated the effect of Sigma-1 Receptor (Sig-1R) stimulation with fluvoxamine on myocardial hypertrophy, cardiac functional recovery and defined mechanisms underlying its cardioprotective action.Methods: Wistar rats subjected to bilateral ovariectomy (OVX) were treated with abdominal aortic banding between the right and left renal arteries. To confirm the cardioprotective role of Sig-1R stimulation, we treated the rats with Sig-1R agonist (fluvoxamine, 0.5 and 1 mg/kg) orally once a day for 4 weeks after the onset of aortic banding.Results: Interestingly, the expression of Sig-1R in the left ventricle (LV) decreased significantly 4 weeks after pressure overload (PO)-induced hypertrophy in OVX rats. The fluvoxamine administration significantly attenuated PO-induced myocardial hypertrophy with concomitant increase in the expression of Sig-1R in LV. Fluvoxamine also attenuated hypertrophy-induced impaired LV functions. The cardioprotective effect of fluvoxamine was nullified by treatme...
Masashi Kawamoto - One of the best experts on this subject based on the ideXlab platform.
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skf 10047 a prototype sigma 1 Receptor agonist augmented the membrane trafficking and uptake activity of the serotonin transporter and its c terminus deleted mutant via a sigma 1 Receptor independent mechanism
Journal of Pharmacological Sciences, 2019Co-Authors: Masaya Asano, Serika Motoike, Chika Yokota, Naoto Usuki, Hikaru Yamamoto, Tomoaki Urabe, Kazusa Katarao, Izumi Hide, Shigeru Tanaka, Masashi KawamotoAbstract:Abstract The serotonin transporter (SERT) is functionally regulated via membrane trafficking. Our previous studies have demonstrated that the SERT C-terminal deletion mutant (SERTΔCT) showed a robust decrease in its membrane trafficking and was retained in the endoplasmic reticulum (ER), suggesting that SERTΔCT is an unfolded protein that may cause ER stress. The Sigma-1 Receptor (SigR1) has been reported to attenuate ER stress via its chaperone activity. In this study, we investigated the effects of SKF-10047, a prototype SigR1 agonist, on the membrane trafficking and uptake activity of SERT and SERTΔCT expressed in COS-7 cells. Twenty-four hours of SKF-10047 treatment (>200 μM) accelerated SERT membrane trafficking and robustly upregulated SERTΔCT activity. Interestingly, these effects of SKF-10047 on SERT functions were also found in cells in which SigR1 expression was knocked down by shRNA, suggesting that SKF-10047 exerted these effects on SERT via a mechanism independent of SigR1. A cDNA array study identified several candidate genes involved in the mechanism of action of SKF-10047. Among them, Syntaxin3, a member of the SNARE complex, was significantly upregulated by 48 h of SKF-10047 treatment. These results suggest that SKF-10047 is a candidate for ER stress relief.
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SKF-10047, a prototype Sigma-1 Receptor agonist, augmented the membrane trafficking and uptake activity of the serotonin transporter and its C-terminus-deleted mutant via a Sigma-1 Receptor-independent mechanism
Elsevier, 2019Co-Authors: Masaya Asano, Serika Motoike, Chika Yokota, Naoto Usuki, Hikaru Yamamoto, Tomoaki Urabe, Kazusa Katarao, Izumi Hide, Shigeru Tanaka, Masashi KawamotoAbstract:The serotonin transporter (SERT) is functionally regulated via membrane trafficking. Our previous studies have demonstrated that the SERT C-terminal deletion mutant (SERTΔCT) showed a robust decrease in its membrane trafficking and was retained in the endoplasmic reticulum (ER), suggesting that SERTΔCT is an unfolded protein that may cause ER stress. The Sigma-1 Receptor (SigR1) has been reported to attenuate ER stress via its chaperone activity. In this study, we investigated the effects of SKF-10047, a prototype SigR1 agonist, on the membrane trafficking and uptake activity of SERT and SERTΔCT expressed in COS-7 cells. Twenty-four hours of SKF-10047 treatment (>200 μM) accelerated SERT membrane trafficking and robustly upregulated SERTΔCT activity. Interestingly, these effects of SKF-10047 on SERT functions were also found in cells in which SigR1 expression was knocked down by shRNA, suggesting that SKF-10047 exerted these effects on SERT via a mechanism independent of SigR1. A cDNA array study identified several candidate genes involved in the mechanism of action of SKF-10047. Among them, Syntaxin3, a member of the SNARE complex, was significantly upregulated by 48 h of SKF-10047 treatment. These results suggest that SKF-10047 is a candidate for ER stress relief. Keywords: Serotonin transporter, Sigma-1 Receptor, Membrane trafficking, SKF-1004
