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

Delprat, Benjamin; Crouzier, Lucie; Su, Tsung‐Ping; Maurice, Tangui

doi:10.1007/978-3-030-12457-1_28

Cited by 59 publications

(53 citation statements)

References 154 publications

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“…The data obtained in laboratory animals are consistent with the distribution of Sigma1R in the human brain [56]. Sigma1R is a resident protein of the endoplasmic reticulum (ER) and is predominantly localized in the cholesterol-rich region of ER mitochondria-associated membranes (MAM) [35,40,57,58]. In this compartment, Sigma1R acts as a chaperone to stabilize IP 3 R3, maintaining Ca 2+ flow from the ER to mitochondria and ATP production [59].…”

Section: Structure and Functional Activity Of The Chaperone Sigma1rsupporting

confidence: 76%

“…To date, the Sigma1R chaperone activity has been established, and a significant body of scientific data on the structure, functional activity, and ligand regulation of Sigma1R has been collected. Most of the studies are systematized and presented in detailed reviews [35,36,[39][40][41][42][43][44]. The human, murine, rat, and guinea pig Sigma1R protein comprises 223 amino acid residues (~25 kDa) that are more than 90% identical.…”

Section: Structure and Functional Activity Of The Chaperone Sigma1rmentioning

confidence: 99%

“…In turn, without the ER stress and in combination with IRE1, BiP itself acts as an ER stress sensor and does not perform its normal chaperone functions [68]. The activity of Sigma1R in the MAM region is significant for the response to ER stress (UPR, unfolded protein response) in pathological conditions [40,69]. The interaction of Sigma1R with Rac1-GTPase influences the redox processes in neurons and the formation of dendritic spines [70,71].…”

Section: Structure and Functional Activity Of The Chaperone Sigma1rmentioning

confidence: 99%

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Chaperone Sigma1R and Antidepressant Effect

Voronin

Vakhitova

Seredenin

2020

IJMS

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This review analyzes the current scientific literature on the role of the Sigma1R chaperone in the pathogenesis of depressive disorders and pharmacodynamics of antidepressants. As a result of ligand activation, Sigma1R is capable of intracellular translocation from the endoplasmic reticulum (ER) into the region of nuclear and cellular membranes, where it interacts with resident proteins. This unique property of Sigma1R provides regulation of various receptors, ion channels, enzymes, and transcriptional factors. The current review demonstrates the contribution of the Sigma1R chaperone to the regulation of molecular mechanisms involved in the antidepressant effect.

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Section: Structure and Functional Activity Of The Chaperone Sigma1rsupporting

confidence: 76%

Section: Structure and Functional Activity Of The Chaperone Sigma1rmentioning

confidence: 99%

Section: Structure and Functional Activity Of The Chaperone Sigma1rmentioning

confidence: 99%

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Chaperone Sigma1R and Antidepressant Effect

Voronin

Vakhitova

Seredenin

2020

IJMS

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“…In patients with early-stage PD, striatal damage is accompanied by a decrease in the Sigma1R level [ 25 ], which corresponds to the high death rate of dopaminergic neurons in Sigmar1 −/− mice [ 23 ]. Intracellular Sigma1Rs are predominantly located within the cholesterol reach region of the endoplasmic reticulum (ER) membrane in contact with mitochondrion (MAM) [ 26 ]. The ligand activation of Sigma1R provides its translocation [ 27 ] and chaperone activity toward multiple proteins of plasmatic, ER, and nucleus membranes [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

Deferred Administration of Afobazole Induces Sigma1R-Dependent Restoration of Striatal Dopamine Content in a Mouse Model of Parkinson’s Disease

Kadnikov

Verbovaya

Воронков

et al. 2020

IJMS

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Previously, we demonstrated that the immediate administration of multitarget anxiolytic afobazole slows down the progression of neuronal damage in a 6-hydroxidodamine (6-OHDA) model of Parkinson’s disease due to the activation of chaperone Sigma1R. The aim of the present study is to evaluate the therapeutic potential of deferred afobazole administration in this model. Male ICR mice received a unilateral 6-OHDA lesion of the striatum. Fourteen days after the surgery, mice were treated with afobazole, selective Sigma1R agonist PRE-084, selective Sigma1R antagonist BD-1047, and a combination of BD-1047 with afobazole or PRE-084 for another 14 days. The deferred administration of afobazole restored the intrastriatal dopamine content in the 6-OHDA-lesioned striatum and facilitated motor behavior in rotarod tests. The action of afobazole accorded with the effect of Sigma1R selective agonist PRE-084 and was blocked by Sigma1R selective antagonist BD-1047. The present study illustrates the Sigma1R-dependent effects of afobazole in a 6-OHDA model of Parkinson’s disease and reveals the therapeutic potential of Sigma1R agonists in treatment of the condition.

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“…The endogenous ligand of S1R has not been unanimously identified yet and along the years it has been discovered that S1R can be activated by some endogenous compounds, like neuropeptides, neurosteroids, N,N-dimethyltryptamine, or by physiological signals like oxidative or endoplasmic reticulum (ER) stress [ 4 , 5 , 6 , 7 ]. S1R is a transmembrane chaperone protein, present in the ER, nucleus and plasma membranes but particularly enriched in mitochondria-associated ER membranes (MAMs) [ 8 , 9 , 10 ]. Modulation of S1R may have a relevant potential from a therapeutic standpoint.…”

Section: Introductionmentioning

confidence: 99%

Setup and Validation of a Reliable Docking Protocol for the Development of Neuroprotective Agents by Targeting the Sigma-1 Receptor (S1R)

Rossino

Rui

Pozzetti

et al. 2020

IJMS

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Sigma-1 receptor (S1R) is a promising molecular target for the development of novel effective therapies against neurodegenerative diseases. To speed up the discovery of new S1R modulators, herein we report the development of a reliable in silico protocol suitable to predict the affinity of small molecules against S1R. The docking method was validated by comparing the computational calculated Ki values of a test set of new aryl-aminoalkyl-ketone with experimental determined binding affinity. The druggability profile of the new compounds, with particular reference to the ability to cross the blood–brain barrier (BBB) was further predicted in silico. Moreover, the selectivity over Sigma-2 receptor (S2R) and N-methyl-D-aspartate (NMDA) receptor, another protein involved in neurodegeneration, was evaluated. 1-([1,1’-biphenyl]-4-yl)-4-(piperidin-1-yl)butan-1-one (12) performed as the best compound and was further investigated for acetylcholinesterase (AchE) inhibitor activity and determination of antioxidant activity mediated by aquaporins (AQPs). With a good affinity against both S1R and NMDA receptor, good selectivity over S2R and favorable BBB penetration potential together with its AChE inhibitory activity and its ability to exert antioxidant effects through modulation of AQPs, 12 represents a viable candidate for further development as a neuroprotective agent.

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

Cited by 59 publications

References 154 publications

Chaperone Sigma1R and Antidepressant Effect

Chaperone Sigma1R and Antidepressant Effect

Deferred Administration of Afobazole Induces Sigma1R-Dependent Restoration of Striatal Dopamine Content in a Mouse Model of Parkinson’s Disease

Setup and Validation of a Reliable Docking Protocol for the Development of Neuroprotective Agents by Targeting the Sigma-1 Receptor (S1R)

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