Sigma Receptor 1 Modulates Endoplasmic Reticulum Stress in Retinal Neurons

Ha, Yonju; Dun, Ying; Thangaraju, Muthusamy; Duplantier, Jennifer; Zheng, Dezhi; Liu, Kebin; Ganapathy, Vadivel; Smith, Sylvia B.

doi:10.1167/iovs.10-5731

Cited by 73 publications

(88 citation statements)

References 45 publications

(62 reference statements)

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“…It is likely that H 2 O 2 also affects this and provides an interesting line of investigation for future studies. The current findings integrate well with data obtained from rat retinal cells and tissue reported by Ha et al (2011). In the rodent system, primary ganglion cells demonstrated increase cell death in response to xanthine:xanthine oxidase, which was employed as an oxidative stress.…”

Section: Discussionsupporting

confidence: 89%

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

Wang

Eldred

Sidaway

et al. 2012

Mechanisms of Ageing and Development

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Section: Discussionsupporting

confidence: 89%

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

Wang

Eldred

Sidaway

et al. 2012

Mechanisms of Ageing and Development

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“…The robust rescue of cone function in rd10 mice treated with (+)-PTZ appears to be attributable (at least in part) to attenuated Müller cell gliosis, reduced microglial activation, and decreased oxidative stress. Sig1R, whose activation also has been reported to attenuate excitotoxicity (13,18), calcium dysregulation (12,17,26), ER stress (12,23,32), and inflammation (15,16,35), constitutes a promising target for pharmacologically treating retinal disease.…”

Section: Discussionmentioning

confidence: 99%

“…Administration of (+)-PTZ is protective against ROS accumulation in several retinal cell types (16,23,(32)(33)(34). We investigated whether (+)-PTZ could attenuate oxidative stress in vivo.…”

Section: Sig1r Activation Attenuates Retinal Müller Cell Gliosis and mentioning

confidence: 99%

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Activation of the molecular chaperone, sigma 1 receptor, preserves cone function in a murine model of inherited retinal degeneration

Wang

Saul

Roon

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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118

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Retinal degenerative diseases are major causes of untreatable blindness, and novel approaches to treatment are being sought actively. Here we explored the activation of a unique protein, sigma 1 receptor (Sig1R), in the treatment of PRC loss because of its multifaceted role in cellular survival. We used Pde6β rd10 (rd10) mice, which harbor a mutation in the rod-specific phosphodiesterase gene Pde6β and lose rod and cone photoreceptor cells (PRC) within the first 6 wk of life, as a model for severe retinal degeneration. Systemic administration of the high-affinity Sig1R ligand (+)-pentazocine [(+)-PTZ] to rd10 mice over several weeks led to the rescue of cone function as indicated by electroretinographic recordings using natural noise stimuli and preservation of cone cells upon spectral domain optical coherence tomography and retinal histological examination. The protective effect appears to result from the activation of Sig1R, because rd10/Sig1R

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“…Enzyme activity was determined in 100 ll reaction volume spectrophotometrically (k = 570 nm). Relative XO activity was calculated as a ratio of emission of treated cells to untreated cells [17]. The experiments were repeated three times.…”

Section: Measurement Of Ros Generationmentioning

confidence: 99%

Hepatocyte growth factor suppresses hypoxia/reoxygenation-induced XO activation in cardiac microvascular endothelial cells

Zhang

Chen

2014

Heart Vessels

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Hypoxia/reoxygenation (H/R) is one of the cellular stresses in pathological conditions, such as myocardial infarction, stroke and organ transplantation. Oxidative stress caused by reactive oxygen species (ROS) is a crucial element of H/R injury in vascular endothelial cells (ECs). Xanthine oxidase (XO) has been recognized to contribute to H/R injury. Of note, xanthine oxidoreductase is synthesized as xanthine dehydrogenase (XDH) and needs to be converted to XO to become a source of superoxide. Hepatocyte growth factor (HGF) has been found to protect ECs against H/R injury. The relation, however, between HGF and XO in ECs under H/R conditions remains to be determined. Primary cultured rat cardiac microvascular endothelial cells (CMECs) were exposed to 4 h of hypoxia and followed by 1 h of reoxygenation. Generation of ROS and cytosolic Ca2+ concentration was measured by flow cytometry qualification of DCFHDA and fluo-3 AM staining cells, respectively. XDH mRNA was qualified by qRT-PCR analysis. XO activity was determined by colorimetric assay and XO protein levels were determined by Western blot. Cell apoptosis was assessed by caspase-3 activity and Annexin V/PI staining. After H/R, cellular ROS production significantly increased. Both XO activity and XO protein increased after H/R. Cellular ROS elevation was inhibited by allopurinol (a potent XO inhibitor), indicting XO accounting for the generation of ROS after H/R. In addition, XDH mRNA increased after H/R, indicating a de novo XDH synthesis, which needs to be converted to XO to become a source of superoxide. Pretreatment of HGF inhibited the elevation of XO activity and XO protein level after H/R; however, HGF has no effect on the increase of XDH mRNA. We also find an increase of the cytosolic Ca2+ in CMECs after H/R. BAPTA-AM, a cell-permeable Ca2+ chelator, prevented the increase of XO activity and XO protein levels, implicating the elevated cytosolic Ca2+ concentration involvement in XO conversion and XO activation. HGF inhibited the elevation of cytosolic Ca2+ concentration in CMECs after H/R. Furthermore, HGF ameliorated H/R-induced CMECs apoptosis. These findings suggest a novel mechanism whereby HGF inhibited XO-generated ROS production after H/R treatment. H/R induces a de novo synthesis of XDH, the XO precursor. In addition, H/R increases cytosolic Ca2+ concentration and promotes a Ca2+ -involved XO conversion and XO activation. HGF has no effect on the increase of XDH mRNA; however, HGF inhibited the elevation of XO protein level and XO activity after H/R in the post-transcriptional level primarily by inhibiting the increase of cytosolic Ca2+ concentration. HGF protects CMECs from H/R-induced apoptosis by inhibiting the elevation of XO protein level and XO activity.

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Sigma Receptor 1 Modulates Endoplasmic Reticulum Stress in Retinal Neurons

Abstract: In retinal neurons, the molecular chaperone σR1 binds BiP under stressful conditions; (+)-pentazocine may exert its effects by dissociating σR1 from BiP. As stress in retinal cells increases, phosphorylation of σR1 is increased, which is attenuated when agonists bind to the receptor.

Cited by 73 publications

References 45 publications

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

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

Activation of the molecular chaperone, sigma 1 receptor, preserves cone function in a murine model of inherited retinal degeneration

Hepatocyte growth factor suppresses hypoxia/reoxygenation-induced XO activation in cardiac microvascular endothelial cells

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