Sigma-1 receptor stimulation protects retinal ganglion cells from ischemia-like insult through the activation of extracellular-signal-regulated kinases 1/2

Mueller, Brett H.; Park, Yong H.; Ying, Hai; Dibas, Adnan; Ellis, Dorette Z.; Clark, Abbot F.; Yorio, Thomas

doi:10.1016/j.exer.2014.10.007

Cited by 27 publications

(45 citation statements)

References 65 publications

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“…Indeed, Sig-1R has been shown to modulate the functions of p38 MAPK [29], ERK1/2 [30] and calcineurin [31], all of which regulate STIM1 phosphorylation [32–34]. Moreover, both STIM1 [33, 35] and Orai1 [36, 37] are known to be negatively regulated by phosphorylation.…”

Section: Resultsmentioning

confidence: 99%

Cocaine inhibits store-operated Ca2+ entry in brain microvascular endothelial cells: critical role for sigma-1 receptors

Brailoiu

Deliu

Console-Bram

et al. 2015

Biochemical Journal

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Sigma-1 receptor (Sig-1R) is an intracellular chaperone protein with many ligands, located at the endoplasmic reticulum. Binding of cocaine to Sig-1R has previously been found to modulate endothelial functions. In the present study, we show that cocaine dramatically inhibits store-operated Ca2+ entry (SOCE), a Ca2+ influx mechanism promoted by depletion of intracellular Ca2+ stores, in rat brain microvascular endothelial cells. Using either Sig-1R shRNA or pharmacological inhibition with the unrelated Sig-1R antagonists BD-1063 and NE-100, we show that cocaine-induced SOCE inhibition is dependent on Sig-1R. In addition to revealing new insight into fundamental mechanisms of cocaine-induced changes in endothelial function, these studies provide an unprecedented role for Sig-1R as a SOCE inhibitor.

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Section: Resultsmentioning

confidence: 99%

Cocaine inhibits store-operated Ca2+ entry in brain microvascular endothelial cells: critical role for sigma-1 receptors

Brailoiu

Deliu

Console-Bram

et al. 2015

Biochemical Journal

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“…Indeed, Sig-1R could induce the activation of astrocyte in this present study ( Figure 2b) and our earlier work (Wang, Jiang, et al, 2019), suggesting tightly association between Sig-1R and CD38. ERK1/2 is an important molecular to rapidly respond Sig-1R-mediated signaling (Mueller et al, 2014;Tan et al, 2010), and also involved in CD38 transcript stability (Deshpande et al, 2018). Hence, ERK1/2 activation could provide possible explanations for Sig-1R-increased CD38 expression (Figure 6a).…”

Section: Discussionmentioning

confidence: 99%

Activation of astrocytic sigma‐1 receptor exerts antidepressant‐like effect via facilitating CD38‐driven mitochondria transfer

Wang

Gao

et al. 2020

Glia

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Despite sigma‐1 receptor (Sig‐1R) is a promising therapeutic target in depression, little is known regarding the cellular mechanisms underlying its antidepressant responses. Here, we demonstrated that astrocyte can be a direct cellular target of Sig‐1R exerting antidepressant‐like effect. In multiple behavioral models including forced swimming test (FST), tail suspension test (TST), open field test (OFT), and chronic unpredictable mild stress (CUMS), inhibition of astrocyte function blocked pharmacological Sig‐1R activation‐induced antidepressant‐like effect, while specific activation of astrocytc Sig‐1R by adeno‐associated virus (AAV) was sufficient to produce antidepressant‐like effect. In depression‐related cellular tests, Sig‐1R agonist or lentivirus‐stimulated astrocyte conditioned medium (ACM) promoted neuronal neurite outgrowth, dendritic branch, and survival. Mechanismly, stimulation of Sig‐1R enhanced the expression of CD38 via activation of extracellular regulated protein kinases 1/2 (ERK1/2), resulting in facilitating mitochondrial transfer from astrocyte. Furthermore, blockage of CD38‐driven astrocyte transferring mitochondria in vivo and in vitro reversed the antidepressant‐like effect of pharmacological Sig‐1R activation. Thus, this study sheds light on the cellular mechanism of Sig‐1R activation producing antidepressant‐like effect. These data present the first evidence that enhancement of Sig‐1R action on astrocytes entirely exerts antidepressant‐like effect, indicating that specific activation of astrocytic Sig‐1R may provide a new approach for antidepressant drug development.

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“…Triethylamine (TEA) was used, as reported previously[4-6], to adjust the pH of the solution to 8-8.5. The reaction was carried out at room temperature under dark for 24 h. The resulting reaction solution was added dropwise into cold ethyl ether and the precipitates were recrystallized in hot 2–propanol.…”

Section: Methodsmentioning

confidence: 99%

“…Ample in vitro [2-6] and in vivo [7-10] evidence indicates that the sigma-1 receptor (S1R) is a potential intervention target for the prevention of RGC death. S1R was discovered to be a ligand-operated chaperone, and when activated, is generally pro-survival[11].…”

Section: Introductionmentioning

confidence: 99%

An intraocular drug delivery system using targeted nanocarriers attenuates retinal ganglion cell degeneration

Zhao

Chen

et al. 2017

Journal of Controlled Release

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Glaucoma is a common blinding disease characterized by loss of retinal ganglion cells (RGCs). To date, there is no clinically available treatment directly targeting RGCs. We aim to develop an RGC-targeted intraocular drug delivery system using unimolecular micelle nanoparticles (unimNPs) to prevent RGC loss. The unimNPs were formed by single/individual multi-arm star amphiphilic block copolymer poly(amidoamine)–polyvalerolactone–poly(ethylene glycol) (PAMAM–PVL–PEG). While the hydrophobic PAMAM–PVL core can encapsulate hydrophobic drugs, the hydrophilic PEG shell provides excellent water dispersity. We conjugated unimNPs with the cholera toxin B domain (CTB) for RGC-targeting and with Cy5.5 for unimNP-tracing. To exploit RGC-protective sigma-1 receptor (S1R), we loaded unimNPs with an endogenous S1R agonist dehydroepiandrosterone (DHEA) as an FDA-approved model drug. These unimNPs produced a steady DHEA release in vitro for over two months at pH 7.4. We then co-injected (mice, intraocular) unimNPs with the glutamate analog N-methyl-D-aspartate (NMDA), which is excito-toxic and induces RGC death. The CTB-conjugated unimNPs (i.e., targeted NPs) accumulated at the RGC layer and effectively preserved RGCs at least for 14 days, whereas the unimNPs without CTB (i.e., non-targeted NPs) showed neither accumulation at nor protection of NMDA-treated RGCs. Consistent with S1R functions, targeted NPs relative to non-targeted NPs showed markedly better inhibitory effects on apoptosis and oxidative/inflammatory stresses in the RGC layer. Hence, the DHEA-loaded, CTB-conjugated unimNPs represent an RGC/S1R dual-targeted nanoplatform that generates an efficacious template for further development of a sustainable intraocular drug delivery system to protect RGCs, which may be applicable to treatments directed at glaucomatous pathology.

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Sigma-1 receptor stimulation protects retinal ganglion cells from ischemia-like insult through the activation of extracellular-signal-regulated kinases 1/2

Cited by 27 publications

References 65 publications

Cocaine inhibits store-operated Ca2+ entry in brain microvascular endothelial cells: critical role for sigma-1 receptors

Cocaine inhibits store-operated Ca2+ entry in brain microvascular endothelial cells: critical role for sigma-1 receptors

Activation of astrocytic sigma‐1 receptor exerts antidepressant‐like effect via facilitating CD38‐driven mitochondria transfer

An intraocular drug delivery system using targeted nanocarriers attenuates retinal ganglion cell degeneration

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