WFS1 protein modulates the free Ca<sup>2+</sup> concentration in the endoplasmic reticulum

Takei, Daisuke; Ishihara, Hideharu; Yamaguchi, Suguru; Yamada, Takahiro; Tamura, Akira; Katagiri, Hideki; Maruyama, Yoshio; Oka, Yoshitomo

doi:10.1016/j.febslet.2006.09.007

Cited by 163 publications

(137 citation statements)

References 24 publications

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“…Later works by other authors reported similar values [4][5][6][7][8]. However, our data here indicate that [Ca 2+ ] ER is higher.…”

Section: Discussionsupporting

confidence: 71%

“…The first measurements of [Ca 2+ ] ER using mutated aequorin, reconstituted with a semi-synthetic coelenterazine with lower relative luminescence intensity (coelenterazine n), were made by us 15 years ago [1][2][3]. This combination of mutated aequorin and coelenterazine n (ER-mutAEQ-n) has been widely used to measure [Ca 2+ ] ER along these years [4][5][6][7][8]. However, it still has some problems that severely limit the results which can be obtained.…”

Section: Introductionmentioning

confidence: 99%

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Ca2+ homeostasis in the endoplasmic reticulum measured with a new low-Ca2+-affinity targeted aequorin

et al. 2013

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a b s t r a c tWe use here a new very low-Ca 2+ -affinity targeted aequorin to measure the [Ca 2+ ] between 0.1 and 3 mM, and was only partially affected by mitochondrial membrane depolarization. Instead, it was significantly reduced by loading cells with chelators, and the fast chelator BAPTA was much more effective than the slow chelator EGTA. This suggests that local [Ca 2+ ] microdomains connecting the store operated Ca 2+ channels with the ER Ca 2+ pumps may be important during refilling.

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“…Later works by other authors reported similar values [4][5][6][7][8]. However, our data here indicate that [Ca 2+ ] ER is higher.…”

Section: Discussionsupporting

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Ca2+ homeostasis in the endoplasmic reticulum measured with a new low-Ca2+-affinity targeted aequorin

et al. 2013

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“…It may regulate ER calcium homeostasis by serving as an ER cation channel [16,17]. Recently the WFS1 protein was also suggested to be a putative chaperone for the Na/K ATPase b1 subunit in the ER [18].…”

Section: Introductionmentioning

confidence: 99%

Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apoptosis in Wfs1 knockout mice

et al. 2009

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Aims/hypothesis The WFS1 gene encodes an endoplasmic reticulum (ER) membrane-embedded protein called Wolfram syndrome 1 protein, homozygous mutations of which cause selective beta cell loss in humans. The function(s) of this protein and the mechanism by which the mutations of this gene cause beta cell death are still not fully understood. We hypothesised that increased insulin demand as a result of obesity/insulin resistance causes ER stress in pancreatic beta cells, thereby promoting beta cell death. Methods We studied the effect of breeding Wfs1 −/− mice on a C57BL/6J background with mild obesity and insulin resistance, by introducing the agouti lethal yellow mutation (A y /a). We also treated the mice with pioglitazone.

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“…WFS1, the other causative gene for Wolfram syndrome, has been shown to be involved in calcium homeostasis (27,28), suggesting that the loss of function of WFS1 may also cause calpain activation. To evaluate this possibility, we measured calpain activation levels in brain tissues from WFS1 brain-specific knockout and control mice.…”

Section: Significancementioning

confidence: 99%

A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome

Kanekura

Hara

et al. 2014

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

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Wolfram syndrome is a genetic disorder characterized by diabetes and neurodegeneration and considered as an endoplasmic reticulum (ER) disease. Despite the underlying importance of ER dysfunction in Wolfram syndrome and the identification of two causative genes, Wolfram syndrome 1 (WFS1) and Wolfram syndrome 2 (WFS2), a molecular mechanism linking the ER to death of neurons and β cells has not been elucidated. Here we implicate calpain 2 in the mechanism of cell death in Wolfram syndrome. Calpain 2 is negatively regulated by WFS2, and elevated activation of calpain 2 by WFS2-knockdown correlates with cell death. Calpain activation is also induced by high cytosolic calcium mediated by the loss of function of WFS1. Calpain hyperactivation is observed in the WFS1 knockout mouse as well as in neural progenitor cells derived from induced pluripotent stem (iPS) cells of Wolfram syndrome patients. A small-scale small-molecule screen targeting ER calcium homeostasis reveals that dantrolene can prevent cell death in neural progenitor cells derived from Wolfram syndrome iPS cells. Our results demonstrate that calpain and the pathway leading its activation provides potential therapeutic targets for Wolfram syndrome and other ER diseases.Wolfram syndrome | endoplasmic reticulum | diabetes | neurodegeneration | treatment

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WFS1 protein modulates the free Ca²⁺ concentration in the endoplasmic reticulum

Cited by 163 publications

References 24 publications

Ca2+ homeostasis in the endoplasmic reticulum measured with a new low-Ca2+-affinity targeted aequorin

Ca2+ homeostasis in the endoplasmic reticulum measured with a new low-Ca2+-affinity targeted aequorin

Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apoptosis in Wfs1 knockout mice

A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome

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WFS1 protein modulates the free Ca2+ concentration in the endoplasmic reticulum

Cited by 163 publications

References 24 publications

Ca2+ homeostasis in the endoplasmic reticulum measured with a new low-Ca2+-affinity targeted aequorin

Ca2+ homeostasis in the endoplasmic reticulum measured with a new low-Ca2+-affinity targeted aequorin

Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apoptosis in Wfs1 knockout mice

A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome

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WFS1 protein modulates the free Ca²⁺ concentration in the endoplasmic reticulum