Chaperone Sigma1R and Antidepressant Effect

Voronin, M. V.; Vakhitova, Yu. V.; Seredenin, S. B.

doi:10.3390/ijms21197088

Cited by 26 publications

(22 citation statements)

References 271 publications

(501 reference statements)

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“…Sigma1R was first cloned by Hanner et al in 1996 [59]. Its pharmacology has been described in detail, most recently in comprehensive reviews [49,51,60]. Sigma1R is an~25 kDa chaperone protein of 223 amino acids.…”

Section: Function Of Sigma1rmentioning

confidence: 99%

“…The crystal structure of the Sigma1R identified by Kruse and colleagues in 2016 revealed one transmembrane domain for each monomer. Sigma1R is an endoplasmic reticulum (ER) chaperone protein localized to the mitochondria-associated membranes (MAMs) [50,51,60,61]. Based on the available evidence, it appears that the diverse functions of Sigma1R are directed toward maintaining calcium homeostasis in the cell.…”

Section: Function Of Sigma1rmentioning

confidence: 99%

“…Sigma1Rs become activated in response to physiological stressors, including the excitatory/inhibitory neuronal imbalances that lead to seizure activity. Sigma1Rs also associate with Rac1-GTPases (hydrolase enzymes of guanosine triphosphate) in dendrites to modulate redox processes in the formation of dendritic spines [60]. As such, Sigma1Rs have been widely investigated as potentially novel targets for treating neurological disorders, including seizure-related disorders [40].…”

Section: Function Of Sigma1rmentioning

confidence: 99%

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An Emerging Role for Sigma-1 Receptors in the Treatment of Developmental and Epileptic Encephalopathies

Martin

Reeder

Sourbron

et al. 2021

IJMS

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Developmental and epileptic encephalopathies (DEEs) are complex conditions characterized primarily by seizures associated with neurodevelopmental and motor deficits. Recent evidence supports sigma-1 receptor modulation in both neuroprotection and antiseizure activity, suggesting that sigma-1 receptors may play a role in the pathogenesis of DEEs, and that targeting this receptor has the potential to positively impact both seizures and non-seizure outcomes in these disorders. Recent studies have demonstrated that the antiseizure medication fenfluramine, a serotonin-releasing drug that also acts as a positive modulator of sigma-1 receptors, reduces seizures and improves everyday executive functions (behavior, emotions, cognition) in patients with Dravet syndrome and Lennox-Gastaut syndrome. Here, we review the evidence for sigma-1 activity in reducing seizure frequency and promoting neuroprotection in the context of DEE pathophysiology and clinical presentation, using fenfluramine as a case example. Challenges and opportunities for future research include developing appropriate models for evaluating sigma-1 receptors in these syndromic epileptic conditions with multisystem involvement and complex clinical presentation.

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Section: Function Of Sigma1rmentioning

confidence: 99%

Section: Function Of Sigma1rmentioning

confidence: 99%

Section: Function Of Sigma1rmentioning

confidence: 99%

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An Emerging Role for Sigma-1 Receptors in the Treatment of Developmental and Epileptic Encephalopathies

Martin

Reeder

Sourbron

et al. 2021

IJMS

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“…When administered 60 min before the test, ISSRs fluvoxamine (30 mg/kg p.o. ), which has the properties of a Sigma1R agonist showed analogous action [ 106 ], similar to paroxetine which has a higher affinity for serotonin and norepinephrine transporters [ 107 ], but significantly less affinity for Sigma1R in comparison with fluvoxamine [ 104 , 108 , 109 ]. It is worth noting that selective Sigma1R antagonists BD-1047 (3 mg/kg i.p.)…”

Section: Discussionmentioning

confidence: 99%

Involvement of Chaperone Sigma1R in the Anxiolytic Effect of Fabomotizole

Voronin

Vakhitova

Tsypysheva

et al. 2021

IJMS

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Sigma-1 receptor (chaperone Sigma1R) is an intracellular protein with chaperone functions, which is expressed in various organs, including the brain. Sigma1R participates in the regulation of physiological mechanisms of anxiety (Su, T. P. et al., 2016) and reactions to emotional stress (Hayashi, T., 2015). In 2006, fabomotizole (ethoxy-2-[2-(morpholino)-ethylthio]benzimidazole dihydrochloride) was registered in Russia as an anxiolytic (Seredenin S. and Voronin M., 2009). The molecular targets of fabomotizole are Sigma1R, NRH: quinone reductase 2 (NQO2), and monoamine oxidase A (MAO-A) (Seredenin S. and Voronin M., 2009). The current study aimed to clarify the dependence of fabomotizole anxiolytic action on its interaction with Sigma1R and perform a docking analysis of fabomotizole interaction with Sigma1R. An elevated plus maze (EPM) test revealed that the anxiolytic-like effect of fabomotizole (2.5 mg/kg i.p.) administered to male BALB/c mice 30 min prior EPM exposition was blocked by Sigma1R antagonists BD-1047 (1.0 mg/kg i.p.) and NE-100 (1.0 mg/kg i.p.) pretreatment. Results of initial in silico study showed that fabomotizole locates in the active center of Sigma1R, reproducing the interactions with the site’s amino acids common for established Sigma1R ligands, with the ΔGbind value closer to that of agonist (+)-pentazocine in the 6DK1 binding site.

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“…More information about the discovery history of sigma-1 receptors has been published ( Ye et al, 2020 ). Sigma-1 receptors are resident proteins of the endoplasmic reticulum (ER) and are predominantly localized in the cholesterol-rich region of ER mitochondria-associated membranes (MAM) ( Schmidt and Kruse, 2019 ; Voronin et al, 2020 ). This protein is identical in peripheral tissues and in the brain, and probably is similar in other tissues as well ( Rousseaux and Greene, 2016 ; Schmidt and Kruse, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Sigma-1 Receptors in Depression: Mechanism and Therapeutic Development

Ren

Wang

Li³

et al. 2022

Front. Pharmacol.

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Depression is the most common type of neuropsychiatric illness and has increasingly become a major cause of disability. Unfortunately, the recent global pandemic of COVID-19 has dramatically increased the incidence of depression and has significantly increased the burden of mental health care worldwide. Since full remission of the clinical symptoms of depression has not been achieved with current treatments, there is a constant need to discover new compounds that meet the major clinical needs. Recently, the roles of sigma receptors, especially the sigma-1 receptor subtype, have attracted increasing attention as potential new targets and target-specific drugs due to their translocation property that produces a broad spectrum of biological functions. Even clinical first-line antidepressants with or without affinity for sigma-1 receptors have different pharmacological profiles. Thus, the regulatory role of sigma-1 receptors might be useful in treating these central nervous system (CNS) diseases. In addition, long-term mental stress disrupts the homeostasis in the CNS. In this review, we discuss the topical literature concerning sigma-1 receptor antidepressant mechanism of action in the regulation of intracellular proteostasis, calcium homeostasis and especially the dynamic Excitatory/Inhibitory (E/I) balance in the brain. Furthermore, based on these discoveries, we discuss sigma-1 receptor ligands with respect to their promise as targets for fast-onset action drugs in treating depression.

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Chaperone Sigma1R and Antidepressant Effect

Cited by 26 publications

References 271 publications

An Emerging Role for Sigma-1 Receptors in the Treatment of Developmental and Epileptic Encephalopathies

An Emerging Role for Sigma-1 Receptors in the Treatment of Developmental and Epileptic Encephalopathies

Involvement of Chaperone Sigma1R in the Anxiolytic Effect of Fabomotizole

Sigma-1 Receptors in Depression: Mechanism and Therapeutic Development

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