Isoform- and Species-specific Control of Inositol 1,4,5-Trisphosphate (IP3) Receptors by Reactive Oxygen Species

Bansághi, Száva; Golenár, Tünde; Madesh, Muniswamy; Csordás, György; RamachandraRao, Satish P.; Sharma, Kumar; Yule, David I.; Joseph, Suresh K.; Hajnóczky, György

doi:10.1074/jbc.m113.504159

Cited by 128 publications

(103 citation statements)

References 49 publications

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“…Similar findings have been reported in HeLa cells exposed to fast H 2 S donors, although in this case IP 3 R1 expression levels were also increased [170]. Interestingly, IP 3 Rs may also be directly affected by reactive oxygen species (ROS) [171]. In intact DT40 cells, superoxide anions caused Ca 2+ release from the ER, likely via a mechanism that sensitizes IP 3 Rs to basal levels of IP 3 signalling.…”

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

confidence: 72%

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 Senescencesupporting

confidence: 72%

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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“…2d, e). This may additionally due to the enhanced coupling between P2YRs and IP 3 Rs or post-translational modifications on IP 3 Rs [53]. The precise mechanisms underlying the heterogeneity of the Ca 2+ responses and function of IP 3 Rs in hESCs and CVPCs remain to be investigated.…”

Section: Discussionmentioning

confidence: 99%

Coupling switch of P2Y-IP3 receptors mediates differential Ca2+ signaling in human embryonic stem cells and derived cardiovascular progenitor cells

Huang

Zhang

et al. 2016

Purinergic Signalling

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“…In addition, the metabolic characterization would also benefit the comparison between DT40 and other cells in terms of metabolic regulation of IP 3 R, i.e. by ROS [17].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

The roles of IP3 receptor in energy metabolic pathways and reactive oxygen species homeostasis revealed by metabolomic and biochemical studies

Jin

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Inositol 1,4,5-trisphosphate receptors (IP(3)Rs) are calcium channels modulating important calcium-mediated processes. Recent studies implicate IP(3)R in cell metabolism, but specific evidence is missing regarding IP(3)R's effects on actual metabolic pathways and key energy metabolites. Here, we applied metabolomics and molecular biology to compare DT40 cell lines devoid of IP(3)R (KO) and its wild-type (WT) counterpart. NMR and LC-MS metabolomic data showed that the KO cell line has a very different basic energy metabolism from the WT cell line, showing enhanced Warburg effect. In particular, the KO cells exhibited significant perturbation in energy charge, reduced glutathione and NADPH ratios with slower cellular growth rate. Subsequent flow cytometry results showed that the KO cell line has a higher level of general reactive oxygen species (ROS) but has a lower level of peroxynitrites. This ROS disturbance could be explained by observing lower expression of superoxide dismutase 2 (SOD2) and unchanged expression of catalase. The higher ROS seems to be involved in the slower growth rate of the KO cells, with an ROS scavenger increasing their growth rate. However, the KO and WT cell lines did not show any noticeable differences in AMPK and phosphorylated AMPK levels, suggesting possible saturation of AMPK-mediated metabolic regulatory circuit in both cells. Overall, our study reveals IP3R's roles in ROS homeostasis and metabolic pathways as well as the effects of its KO on cellular phenotypes.

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Isoform- and Species-specific Control of Inositol 1,4,5-Trisphosphate (IP3) Receptors by Reactive Oxygen Species

Cited by 128 publications

References 49 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

Coupling switch of P2Y-IP3 receptors mediates differential Ca2+ signaling in human embryonic stem cells and derived cardiovascular progenitor cells

The roles of IP3 receptor in energy metabolic pathways and reactive oxygen species homeostasis revealed by metabolomic and biochemical studies

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