Novel mechanism of increased Ca2+ release following oxidative stress in neuronal cells involves type 2 inositol-1,4,5-trisphosphate receptors

Kaja, Simon; Duncan, R. Scott; Longoria, Sandra; Hilgenberg, Jill D.; Payne, Andrew J.; Desai, Nirupa; Parikh, Ruby A.; Burroughs, Stephanie L.; Gregg, Elaine V.; Goad, Daryl L.; Koulen, Peter

doi:10.1016/j.neuroscience.2010.11.010

Cited by 37 publications

(37 citation statements)

References 61 publications

(98 reference statements)

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“…lncreasing oxidative stress in a neuronal cell line exposed to sub-lethal concentrations of tert-butyl hydroperoxide-mediated oxidative stress led to prominent upregulation of IP 3 R2 mRNA and protein levels, while IP 3 R1 and IP 3 R3-expression levels remained unaltered [38]. Consistent with elevated IP 3 R expression levels, Ca 2+ release from the nucleoplasm in response to a cell-permeable IP 3 ester was strongly potentiated in tert-butyl hydroperoxide-treated cells.…”

Section: The Role Of Ip3r2 In Cell Death and In Senescencementioning

confidence: 99%

See 1 more Smart Citation

The type 2 inositol 1,4,5-trisphosphate receptor, emerging functions for an intriguing Ca2+-release channel

Vervloessem

Yule

Bultynck

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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The inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) type 2 (IP3R2) is an intracellular Ca2+-release channel located on the endoplasmic reticulum (ER). It displays in many cell types a predominantly perinuclear or even nuclear localization. IP3R2 is characterized by a high sensitivity to both IP3 and ATP and is biphasically regulated by Ca2+. Interestingly, ATP stimulates IP3R2 independently of the cytosolic [Ca2+]. Furthermore, IP3R2 is modulated by phosphorylation events mediated by e.g. protein kinase A, Ca2+/calmodulin-dependent kinase II and protein kinase C. In addition to its regulation by protein kinase A, IP3R2 forms a complex with adenylate cyclase 6 and is directly regulated by cAMP, thereby linking in a new way Ca2+-dependent and cAMP-dependent signalling. Finally, in the ER, IP3R2 is less mobile than the other IP3R isoforms, while its functional properties appear dominant in heterotetramers. These properties make the IP3R2 a Ca2+ channel with exquisite properties for setting up intracellular Ca2+ signals with unique characteristics. IP3R2 plays a crucial role in the function of secretory cell types (e.g. pancreatic acinar cells, hepatocytes, salivary gland, eccrine sweat gland). In cardiac myocytes, the role of IP3R2 appears more complex, because, together with IP3R1, it is needed for normal cardiogenesis, while its aberrant activity is implicated in cardiac hypertrophy and arrhythmias. Moreover, IP3R2 expression is driven by IP3-induced Ca2+ release leading to a self-perpetuating system of cardiac hypertrophy. Most importantly, its high sensitivity to IP3 makes IP3R2 a target for anti-apoptotic proteins (e.g. Bcl-2) in B-cell cancers. Disrupting IP3R/Bcl-2 interaction therefore leads in those cells to increased Ca2+ release and apoptosis. Intriguingly, IP3R2 is not only implicated in apoptosis but also in the induction of senescence, another tumour-suppressive mechanism. These results were the first to unravel the physiological and pathophysiological role of IP3R2 and we anticipate that further progress will soon be made in understanding the function of IP3R2 in various tissues and organs.

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Section: The Role Of Ip3r2 In Cell Death and In Senescencementioning

confidence: 99%

“…Second, in dendritic cells, IP 3 R2 expression is controlled by the transcription factor ETS1, which itself depends on protein kinase B (AKT/PKB) 2 [37]. Finally, although not yet understood at the mechanistic level, in the HT22 cell line, oxidative stress leads to a specific upregulation of IP 3 R2 [38] (see section 5).…”

Section: Introductionmentioning

confidence: 99%

The type 2 inositol 1,4,5-trisphosphate receptor, emerging functions for an intriguing Ca2+-release channel

Vervloessem

Yule

Bultynck

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…This type of degeneration is often associated with acute or progressive non-apoptotic (caspase-3 and TUNEL negative) cell death (Yang et al, 2008; Kaja et al, 2011). Furthermore, the large assemblies of dilated and vesiculated endoplasmic reticulum cisterns, which are major sites of dendritic calcium storage, point to severe disturbance of calcium clearance mechanisms that may exacerbate cell stress and cause a toxic cascade (Hoyer-Hansen et al, 2007; Ivannikov et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

The Spontaneous Ataxic Mouse Mutant Tippy is Characterized by a Novel Purkinje Cell Morphogenesis and Degeneration Phenotype

et al. 2015

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This study represents the first detailed analysis of the spontaneous neurological mouse mutant, tippy, uncovering its unique cerebellar phenotype. Homozygous tippy mutant mice are small, ataxic and die around weaning. Although the cerebellum shows grossly normal foliation, tippy mutants display a complex cerebellar Purkinje cell phenotype consisting of abnormal dendritic branching with immature spine features and patchy, non-apoptotic cell death that is associated with widespread dystrophy and degeneration of the Purkinje cell axons throughout the white matter, the cerebellar nuclei and the vestibular nuclei. Moderate anatomical abnormalities of climbing fiber innervation of tippy mutant Purkinje cells were not associated with changes in climbing fiber-EPSC amplitudes. However, decreased ESPC amplitudes were observed in response to parallel fiber stimulation and correlated well with anatomical evidence for patchy dark cell degeneration of Purkinje cell dendrites in the molecular layer. The data suggest that the Purkinje neurons are a primary target of the tippy mutation. Furthermore, we hypothesize that the Purkinje cell axonal pathology together with disruptions in the balance of climbing fiber and parallel fiber Purkinje cell input in the cerebellar cortex underlie the ataxic phenotype in these mice. The constellation of Purkinje cell dendritic malformation and degeneration phenotypes in tippy mutants is unique and has not been reported in any other neurologic mutant. Fine mapping of the tippy mutation to a 2.1MB region of distal chromosome 9, which does not encompass any gene previously implicated in cerebellar development or neuronal degeneration, confirms that the tippy mutation identifies novel biology and gene function.

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“…The MTT assay was performed essentially as described by us previously for HT-22 cells and primary cortical neuron culture (Burroughs et al, 2012; Kaja et al, 2011). Briefly, media was aspirated from the cells and replaced with 100 μl of 1.2 mM MTT in HBSS with calcium and magnesium (Lonza, Walkersville, MD) supplemented with 10 mM 4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid (HEPES) at pH 7.3.…”

Section: Methodsmentioning

confidence: 99%

An optimized lactate dehydrogenase release assay for screening of drug candidates in neuroscience

Kaja

Payne

Singh

et al. 2015

Journal of Pharmacological and Toxicological Methods

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Background Quantification of lactate dehydrogenase (LDH) release is a widely accepted assay for the quantitative determination of cell viability and late-stage apoptosis. Major disadvantages of commercially available LDH assay kits include proprietary formulations, limited options for optimization and high cost, all resulting in limited reproducibility in research applications. New Method Here, we describe a novel, custom LDH assay suitable in the context of plate reader-based screening of drug candidates for glioprotection, but with wide applicability to other cell types and experimental paradigms. Results We developed a novel and highly reproducible LDH release assay that is more cost-effective than commercially available assays with comparable performance. The assay was validated by assessing 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid antioxidant protection against tert-butylhydroperoxide-induced oxidative stress in C6 astroglioma cells. Assay performance was validated by direct comparison and compatible with other methods of measuring cellular viability, namely 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and 6-carboxy-2′, 7′ dichlorodihydrofluorescein diacetate assays. Comparison with Existing Method(s) There was no statistically significant difference between results obtained with the novel custom assay and a commercially available assay CytoTox96® (Promega, Madison, WI). Conclusions The novel custom LDH release assay allows the reproducible quantification of cell viability and is highly cost-effective when compared to commercially available assays (approximately 25 times cheaper). In addition and in contrast to commercially available assays, the identification and detailed description of all assay components and procedures provide greater control over experimental conditions and design. We provide a detailed standard operating procedure permitting our novel assay to be readily adapted depending on experimental requirements.

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Novel mechanism of increased Ca2+ release following oxidative stress in neuronal cells involves type 2 inositol-1,4,5-trisphosphate receptors

Cited by 37 publications

References 61 publications

The type 2 inositol 1,4,5-trisphosphate receptor, emerging functions for an intriguing Ca2+-release channel

The type 2 inositol 1,4,5-trisphosphate receptor, emerging functions for an intriguing Ca2+-release channel

The Spontaneous Ataxic Mouse Mutant Tippy is Characterized by a Novel Purkinje Cell Morphogenesis and Degeneration Phenotype

An optimized lactate dehydrogenase release assay for screening of drug candidates in neuroscience

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