Drop in endo/sarcoplasmic calcium precedes the unfolded protein response in Brefeldin A-treated vascular smooth muscle cells

Ziomek, Gabriela; Breemen, Cornelis van; Esfandiarei, Mitra

doi:10.1016/j.ejphar.2015.07.026

Cited by 3 publications

(4 citation statements)

References 38 publications

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“…Calcium signals were quantitatively measured as described in the Materials and Methods. Upon treatment, intracellular calcium levels noticeably increased in both normal and SMA fibroblasts ( Figure 4 A,B), and the magnitude of calcium increase was similar to that previously reported [ 32 ]. There was no significant difference between normal and SMA fibroblasts in the amplitude of calcium increase ( Figure 4 C).…”

Section: Resultssupporting

confidence: 89%

“…Given that these two chemicals have different modes of ER stress induction and that calcium is more crucial for the function of thapsigargin, we hypothesized that calcium was an important mediator in BFA’s splicing regulatory function. This hypothesis is supported by a recent report that BFA transiently induces calcium efflux from the ER and increases intracellular calcium levels [ 32 ].…”

Section: Discussionsupporting

confidence: 70%

“…The ER stress-inducing mechanism of thapsigargin is directly related to an increase in cytosolic calcium levels by inhibiting calcium reuptake into the ER/sarcoplasmic reticulum (SR) [ 30 ], whereas that of tunicamycin is related to the inhibition of protein glycosylation [ 31 ]. Moreover, according to a recent report [ 32 ], short exposure to BFA transiently increases the level of cytosolic calcium in smooth muscle cells. These observations raised the possibility that BFA might act on the expression of SMN protein by modulating cytosolic calcium levels.…”

Section: Resultsmentioning

confidence: 99%

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Regulation of Survival Motor Neuron Gene Expression by Calcium Signaling

Choi

Yang

Baek

et al. 2021

IJMS

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Spinal muscular atrophy (SMA) is caused by homozygous survival of motor neurons 1 (SMN1) gene deletion, leaving a duplicate gene, SMN2, as the sole source of SMN protein. However, a defect in SMN2 splicing, involving exon 7 skipping, results in a low level of functional SMN protein. Therefore, the upregulation of SMN protein expression from the SMN2 gene is generally considered to be one of the best therapeutic strategies to treat SMA. Most of the SMA drug discovery is based on synthetic compounds, and very few natural compounds have been explored thus far. Here, we performed an unbiased mechanism-independent and image-based screen of a library of microbial metabolites in SMA fibroblasts using an SMN-specific immunoassay. In doing so, we identified brefeldin A (BFA), a well-known inhibitor of ER-Golgi protein trafficking, as a strong inducer of SMN protein. The profound increase in SMN protein was attributed to, in part, the rescue of the SMN2 pre-mRNA splicing defect. Intriguingly, BFA increased the intracellular calcium concentration, and the BFA-induced exon 7 inclusion of SMN2 splicing, was abrogated by the depletion of intracellular calcium and by the pharmacological inhibition of calcium/calmodulin-dependent kinases (CaMKs). Moreover, BFA considerably reduced the expression of Tra2-β and SRSF9 proteins in SMA fibroblasts and enhanced the binding of PSF and hnRNP M to an exonic splicing enhancer (ESE) of exon 7. Together, our results demonstrate a significant role for calcium and its signaling on the regulation of SMN splicing, probably through modulating the expression/activity of splicing factors.

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Section: Resultssupporting

confidence: 89%

Section: Discussionsupporting

confidence: 70%

Section: Resultsmentioning

confidence: 99%

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Regulation of Survival Motor Neuron Gene Expression by Calcium Signaling

Choi

Yang

Baek

et al. 2021

IJMS

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“…Tunicamycin inhibits N‐linked glycosylation of nascent proteins, resulting in an accumulation of unfolded proteins within ER and the induction of ER stress . Brefeldin A induces ER stress via the accumulation of unfolded proteins within the ER lumen by blocking protein transport to the Golgi apparatus . In contrast, endogenous chaperones, such as GRP78 or oxygen‐regulated protein 150 (ORP150), and several low molecular weight compounds called chemical chaperones, particularly 4‐phenyl butyric acid (4‐PBA) and tauroursodeoxycholic acid (TUDCA), are used to enhance the ER folding capacity, stabilize the protein conformation in the ER and facilitate the removal of mutant proteins; thus, these molecules represent potential agents for mitigating ER stress .…”

Section: Endoplasmic Reticulum Stress: An Overviewmentioning

confidence: 99%

Hypothalamic endoplasmic reticulum stress as a key mediator of obesity‐induced leptin resistance

Liu

Guo

et al. 2018

Obesity Reviews

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Obesity is an epidemic disease that is increasing worldwide and is a major risk factor for many metabolic diseases. However, effective agents for the prevention or treatment of obesity remain limited. Therefore, it is urgent to clarify the pathophysiological mechanisms underlying the development and progression of obesity and exploit potential agents to cure and prevent this disease. According to a recent study series, obesity is associated with the development of endoplasmic reticulum stress and the activation of its stress responses (unfolded protein response) in metabolically active tissues, which contribute to the development of obesity-related insulin and leptin resistance, inflammation and energy imbalance. Hypothalamic endoplasmic reticulum stress is the central mechanism underlying the development of obesity-associated leptin resistance and disruption of energy homeostasis; thus, targeting endoplasmic reticulum stress offers a promising therapeutic strategy for improving leptin sensitivity, increasing energy expenditure and ultimately combating obesity. In this review, we highlight the relationship between and mechanism underlying hypothalamic endoplasmic reticulum stress and obesity-associated leptin resistance and energy imbalance and provide new insight regarding strategies for the treatment of obesity.

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