Endoplasmic reticulum Ca2+ release through ryanodine and IP3 receptors contributes to neuronal excitotoxicity

Ruiz, Asier; Matute, Carlos; Alberdi, Elena

doi:10.1016/j.ceca.2009.08.005

Cited by 109 publications

(89 citation statements)

References 59 publications

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“…RANKL-RANK signaling triggers Ca 2+ influx from the intracellular storage sites in the ER primarily through ITPR2 and ITPR3 and activates the Ca 2+ -dependent phosphatase calcineurin (23,25,31), which is essential for the activation of the transcription factor NFATc1. The fluctuation of Ca 2+ levels in the ER lumen results in ER stress (32,33), which raises the possibility that Ca 2+ outflow from the ER lumen triggered by RANKL-RANK signaling indirectly activates IRE1α. To test this idea, we asked whether the stimulation of ITPRs using ATP, an agonist for phospholipase C-coupled P2Y receptor (34,35), induces ER stress in BMMs and activates IRE1α.…”

Section: The Activation Of Ire1α During Osteoclastogenesis Is Dependementioning

confidence: 99%

IRE1α/XBP1-mediated branch of the unfolded protein response regulates osteoclastogenesis

Tohmonda¹,

Yoda²,

Iwawaki³

et al. 2015

J. Clin. Invest.

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(T. Tohmonda).lowed by Alexa Fluor 488-conjugated anti-rabbit IgG (Invitrogen); nuclei were counterstained with DAPI. Images of the cells were acquired with Olympus DP controller software via an Olympus DP70 camera mounted on an Olympus IX71 microscope at room temperature. The objective was a ×100 APO/1.65 NA lens. Images were processed with Adobe Photoshop CS6 for contrast correction and to generate merged images.Statistics. All statistical analyses were performed using Prism 6 (GraphPad Software). Two-tailed Student's t tests for 2 samples assuming equal variances were used to calculate the P values. P < 0.05 was considered significant.Study approval. All of the animal experiments in this study were approved by the Institutional Animal Care and Use Committee of the

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Section: The Activation Of Ire1α During Osteoclastogenesis Is Dependementioning

confidence: 99%

IRE1α/XBP1-mediated branch of the unfolded protein response regulates osteoclastogenesis

Tohmonda¹,

Yoda²,

Iwawaki³

et al. 2015

J. Clin. Invest.

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“…Moreover, RyR-mediated Ca 2+ signaling has been implicated in ATP production and metabolic flexibility in the heart (Bround et al, 2013). Other studies have implicated RyRs in the regulation of apoptosis (Kim et al, 2002) and ER-stressmediated cell death (Luciani et al, 2009;Ruiz et al, 2009) in various cell types, including neurons and pancreatic b cells. The Bcl-2-RyR interaction described here could therefore provide an important regulatory mechanism by which RyR activity controls cell fate.…”

Section: K17dmentioning

confidence: 99%

Bcl-2 binds to and inhibits ryanodine receptors

Vervliet¹,

Decrock²,

Molgó³

et al. 2014

Journal of Cell Science

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The anti-apoptotic B-cell lymphoma-2 (Bcl-2) protein not only counteracts apoptosis at the mitochondria by scaffolding proapoptotic Bcl-2-family members, but also acts at the endoplasmic reticulum, thereby controlling intracellular Ca 2+ dynamics. Bcl-2 inhibits Ca 2+ release by targeting the inositol 1,4,5-trisphosphate receptor (IP 3 R). Sequence analysis has revealed that the Bcl-2-binding site on the IP 3 R displays strong similarity with a conserved sequence present in all three ryanodine receptor (RyR) isoforms. We now report that Bcl-2 co-immunoprecipitated with RyRs in ectopic expression systems and in native rat hippocampi, indicating that endogenous RyR-Bcl-2 complexes exist. Purified RyR domains containing the putative Bcl-2-binding site bound fulllength Bcl-2 in pulldown experiments and interacted with the BH4 domain of Bcl-2 in surface plasmon resonance (SPR) experiments, suggesting a direct interaction. Exogenous expression of fulllength Bcl-2 or electroporation loading of the BH4 domain of Bcl-2 dampened RyR-mediated Ca 2+ release in HEK293 cell models.Finally, introducing the BH4-domain peptide into hippocampal neurons through a patch pipette decreased RyR-mediated Ca 2+ release. In conclusion, this study identifies Bcl-2 as a new inhibitor of RyR-based intracellular Ca 2+ -release channels.

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“…ER stress leads to release of Ca 2+ from the ER via both ryanodine receptors and inositol trisphosphate receptors (IP3R) leading to mitochondrial Ca 2+ overload and activation of apoptosis [53]. Excessive increases in matrix Ca 2+ alter the permeability of mitochondria and finally open the MPT pore [48], causing release of cytochrome c [54] and other pro-apoptotic factors into the cytoplasm.…”

Section: B Cerebral Ischemia and Mirnasmentioning

confidence: 99%

microRNAs: Innovative Targets for Cerebral Ischemia and Stroke

Yu¹,

Stary²,

Yang³

et al. 2012

CDT

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Stroke is one of the leading causes of death and disability worldwide. Because stroke is a multifactorial disease with a short therapeutic window many clinical stroke trials have failed and the only currently approved therapy is thrombolysis. MicroRNAs (miRNA) are endogenously expressed noncoding short single-stranded RNAs that play a role in the regulation of gene expression at the post-transcriptional level, via degradation or translational inhibition of their target mRNAs. The study of miRNAs is rapidly growing and recent studies have revealed a significant role of miRNAs in ischemic disease. miRNAs are especially important candidates for stroke therapeutics because of their ability to simultaneously regulate many target genes and since to date targeting single genes for therapeutic intervention has not yet succeeded in the clinic. Although there are already quite a few review articles about miRNA in ischemic heart disease, much less is currently known about miRNAs in cerebral ischemia. This review summarizes current knowledge about miRNAs and cerebral ischemia, focusing on the role of miRNAs in ischemia, both changes in expression and identification of potential targets, as well as the potential of miRNAs as biomarkers and therapeutic targets in cerebral ischemia.

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Endoplasmic reticulum Ca2+ release through ryanodine and IP3 receptors contributes to neuronal excitotoxicity

Cited by 109 publications

References 59 publications

IRE1α/XBP1-mediated branch of the unfolded protein response regulates osteoclastogenesis

IRE1α/XBP1-mediated branch of the unfolded protein response regulates osteoclastogenesis

Bcl-2 binds to and inhibits ryanodine receptors

microRNAs: Innovative Targets for Cerebral Ischemia and Stroke

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