scholarly journals The Common Inhalational Anesthetic Isoflurane Induces Apoptosis via  Activation of Inositol 1,4,5-Trisphosphate Receptors

2008 ◽  
Vol 108 (2) ◽  
pp. 251-260 ◽  
Author(s):  
Huafeng Wei ◽  
Ge Liang ◽  
Hui Yang ◽  
Qiujun Wang ◽  
Brian Hawkins ◽  
...  
Keyword(s):  
Calcium Release ◽  
B Lymphocyte ◽  
Receptor Activity ◽  
Wild Type ◽  
Ip3 Receptors ◽  
Ip3 Receptor ◽  
Knock Out ◽  
Inositol 1,4,5 Trisphosphate ◽  
Induced Apoptosis ◽  
Er Membrane

Background Isoflurane induces cell apoptosis by an unknown mechanism. The authors hypothesized that isoflurane activates inositol 1,4,5-trisphosphate (IP3) receptors on the endoplasmic reticulum (ER) membrane, causing excessive calcium release, triggering apoptosis. Methods The authors determined isoflurane-induced cytotoxicity by measuring caspase-3 activity, lactate dehydrogenase release, MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt) reduction, and imaging analysis of cell damage markers (annexin V and propidium iodide staining) in different cell types. The authors used the chicken B lymphocyte with a total knock-out of IP3 receptors, PC12 cells with elevated IP3 receptor activity (transfected with L286V presenilin 1), striatal cells with a knock-in of Q111 Huntingtin, and each cell line's corresponding wild-type controls. The authors also measured the isoflurane-evoked changes of calcium concentration in cytosol and/or mitochondria in these cells. Results Isoflurane induced apoptosis concentration- and time-dependently, and sequentially elevated cytosolic and then mitochondrial calcium in the chicken B-lymphocyte wild-type but not the IP3 receptor total knock-out cells. Thapsigargin, a calcium adenosine triphosphatase inhibitor on ER membranes, induced apoptosis and elevations of calcium in cytosol and mitochondria in both chicken B-lymphocyte wild-type and IP3 receptor total knock-out cells. Isoflurane induced significantly more neurotoxicity and greater calcium release from the ER in L286V PC12 and Q111 Huntingtin striatal cells than in their corresponding wild-type controls, both of which were significantly inhibited by the IP3 receptor antagonist xestospongin C. Conclusion These findings suggest that isoflurane activates the ER membrane IP3 receptor, producing excessive calcium release and triggering apoptosis. Neurons with enhanced IP3 receptor activity, as in certain cases of familial Alzheimer or Huntington disease, may be especially vulnerable to isoflurane cytotoxicity.

scholarly journals Inhalational Anesthetics Induce Cell Damage by Disruption of Intracellular Calcium Homeostasis with Different Potencies

2008 ◽  
Vol 109 (2) ◽  
pp. 243-250 ◽  
Author(s):  
Hui Yang ◽  
Ge Liang ◽  
Brian J. Hawkins ◽  
Muniswamy Madesh ◽  
Andrew Pierwola ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Calcium Release ◽  
Cell Damage ◽  
Annexin V ◽  
Wild Type ◽  
Ip3 Receptors ◽  
Ip3 Receptor ◽  
Minimal Alveolar Concentration ◽  
Inhalational Anesthetics ◽  
Excessive Activation

Background The authors hypothesized that inhalational anesthetics induced cell damage by causing abnormal calcium release from the endoplasmic reticulum via excessive activation of inositol 1,4,5-trisphosphate (IP3) receptors, with isoflurane having greater potency than sevoflurane or desflurane. Methods The authors treated DT40 chicken B lymphocytes with total IP3 receptor knockout or their corresponding wild-type control cells with equipotent exposure to isoflurane, sevoflurane, and desflurane. The authors then determined the degree of cell damage by counting the percentage of annexin V- or propidium iodide-positively stained cells or measuring caspase-3 activity. They also studied the changes of calcium concentrations in the endoplasmic reticulum, cytosol, and mitochondria evoked by equipotent concentrations of isoflurane, sevoflurane, and desflurane in both types of DT40 cells. Results Prolonged use of 2 minimal alveolar concentration sevoflurane or desflurane (24 h) induced significant cell damage only in DT40 wild-type and not in IP3 receptor total knockout cells, but with significantly less potency than isoflurane. In accord, all three inhalational anesthetics induced significant decrease of calcium concentrations in the endoplasmic reticulum, accompanied by a subsequent significant increase in the cytosol and mitochondrial calcium concentrations only in DT40 wild-type and not in IP3 receptor total knockout cells. Isoflurane treatment showed significantly greater potency of effect than sevoflurane or desflurane. Conclusion Inhalational anesthetics may induce cell damage by causing abnormal calcium release from the endoplasmic reticulum via excessive activation of IP3 receptors. Isoflurane has greater potency than sevoflurane or desflurane to cause calcium release from the endoplasmic reticulum and to induce cell damage.

Helicobacter pylori γ-glutamyl transpeptidase-induced Ca2+ release via PLC–IP3 receptors in AGS cells

2014 ◽  
Vol 60 (12) ◽  
pp. 865-868 ◽  
Author(s):  
Eun-Hee Park ◽  
Jung-Min Kim ◽  
Kyung-Mi Kim ◽  
Dawon Kang ◽  
Young-Ah Cho ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Dependent Manner ◽  
Ip3 Receptors ◽  
Ip3 Receptor ◽  
Ags Cells ◽  
Inositol 1,4,5 Trisphosphate ◽  
Intracellular Ca ◽  
Induced Apoptosis ◽  
Glutamyl Transpeptidase ◽  
Dose Dependent

In our previous study, γ-glutamyl transpeptidase (GGT) isolated from Helicobacter pylori induced apoptosis of AGS cells. Here, we investigate Ca2+ effects on GGT-induced apoptosis. The GGT transiently and significantly increased intracellular Ca2+ concentration ([Ca2+]i) in AGS cells in a dose-dependent manner (P < 0.05). The GGT-induced Ca2+ increase resulted from Ca2+ influx and release through the phospholipase C – inositol 1,4,5-trisphosphate (PLC–IP3) pathway. The GGT-induced apoptosis was significantly reduced by treatment with U73122 (a PLC inhibitor) and xestospongin (an IP3 receptor antagonist) (P < 0.05). These results indicate that GGT could induce apoptosis of AGS cells by high levels of [Ca2+]i.

scholarly journals Inositol 1,4,5-trisphosphate–induced Calcium Release Is Necessary for Generating the Entire Light Response of Limulus Ventral Photoreceptors

2003 ◽  
Vol 121 (5) ◽  
pp. 441-449 ◽  
Author(s):  
Alan Fein
Keyword(s):  
Calcium Release ◽  
Cyclopiazonic Acid ◽  
Light Response ◽  
Calcium Stores ◽  
Ip3 Receptor ◽  
Treatment Results ◽  
Light Responses ◽  
Calcium Buffer ◽  
Pressure Injection ◽  
Inositol 1,4,5 Trisphosphate

The experiments reported here were designed to answer the question of whether inositol 1,4,5-trisphosphate (IP3)-induced calcium release is necessary for generating the entire light response of Limulus ventral photoreceptors. For this purpose the membrane-permeable IP3 receptor antagonist 2-aminoethoxydiphenyl borate (2APB) (Maruyama, T., T. Kanaji, S. Nakade, T. Kanno, and K. Mikoshiba. 1997. J. Biochem. (Tokyo). 122:498–505) was used. Previously, 2APB was found to inhibit the light activated current of Limulus ventral photoreceptors and reversibly inhibit both light and IP3 induced calcium release as well as the current activated by pressure injection of calcium into the light sensitive lobe of the photoreceptor (Wang, Y., M. Deshpande, and R. Payne. 2002. Cell Calcium. 32:209). In this study 2APB was found to inhibit the response to a flash of light at all light intensities and to inhibit the entire light response to a step of light, that is, both the initial transient and the steady-state components of the response to a step of light were inhibited. The light response in cells injected with the calcium buffer 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (BAPTA) was reversibly inhibited by 2APB, indicating that these light responses result from IP3-mediated calcium release giving rise to an increase in Cai. The light response obtained from cells after treatment with 100 μM cyclopiazonic acid (CPA), which acts to empty intracellular calcium stores, was reversibly inhibited by 2APB, indicating that the light response after CPA treatment results from IP3-mediated calcium release and a consequent rise in Cai. Together these findings imply that IP3-induced calcium release is necessary for generating the entire light response of Limulus ventral photoreceptors.

scholarly journals Specific expression and function of inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) in wild type and knock-out mice

2016 ◽  
Vol 62 ◽  
pp. 1-10 ◽  
Author(s):  
Ariane Scoumanne ◽  
Patricia Molina-Ortiz ◽  
Daniel Monteyne ◽  
David Perez-Morga ◽  
Christophe Erneux ◽  
...  
Keyword(s):  
Wild Type ◽  
Specific Expression ◽  
Knock Out ◽  
Kinase C ◽  
Inositol 1,4,5 Trisphosphate ◽  
Knock Out Mice ◽  
And Function

Regulation of Ca2+-release-activated Ca2+ current (Icrac) by ryanodine receptors in inositol 1,4,5-trisphosphate-receptor-deficient DT40 cells

2001 ◽  
Vol 360 (1) ◽  
pp. 17-22 ◽  
Author(s):  
Kirill KISELYOV ◽  
Dong Min SHIN ◽  
Nikolay SHCHEYNIKOV ◽  
Tomohiro KUROSAKI ◽  
Shmuel MUALLEM
Keyword(s):  
Time Course ◽  
Ryanodine Receptors ◽  
Cell Types ◽  
Ruthenium Red ◽  
General Mechanism ◽  
Inward Rectification ◽  
Wild Type ◽  
Ip3 Receptor ◽  
Inositol 1,4,5 Trisphosphate ◽  
Dt40 Cells

Persistence of capacitative Ca2+ influx in inositol 1,4,5-trisphosphate (IP3) receptor (IP3R)-deficient DT40 cells (DT40IP3R-/−) raises the question of whether gating of Ca2+-release activated Ca2+ current (Icrac) by conformational coupling to Ca2+-release channels is a general mechanism of gating of these channels. In the present work we examined the properties and mechanism of activation of Icrac Ca2+ current in wild-type and DT40IP3R-/− cells. In both cell types passive depletion of internal Ca2+ stores by infusion of EGTA activated a Ca2+ current with similar characteristics and time course. The current was highly Ca2+-selective and showed strong inward rectification, all typical of Icrac. The activator of ryanodine receptor (RyR), cADP-ribose (cADPR), facilitated activation of Icrac, and the inhibitors of the RyRs, 8-N-cADPR, ryanodine and Ruthenium Red, all inhibited Icrac activation in DT40IP3R-/− cells, even after complete depletion of intracellular Ca2+ stores by ionomycin. Wild-type and DT40IP3R-/− cells express RyR isoforms 1 and 3. RyR levels were adapted in DT40IP3R-/− cells to a lower RyR3/RyR1 ratio than in wild-type cells. These results suggest that IP3Rs and RyRs can efficiently gate Icrac in DT40 cells and explain the persistence of Icrac gating by internal stores in the absence of IP3Rs.

scholarly journals Agonist-dependent Phosphorylation of the Inositol 1,4,5-Trisphosphate Receptor

1999 ◽  
Vol 113 (6) ◽  
pp. 851-872 ◽  
Author(s):  
Andrew P. LeBeau ◽  
David I. Yule ◽  
Guy E. Groblewski ◽  
James Sneyd
Keyword(s):  
Acinar Cells ◽  
Calcium Oscillations ◽  
Pancreatic Acinar Cells ◽  
Ip3 Receptors ◽  
Ip3 Receptor ◽  
Open Probability ◽  
Probability Curve ◽  
Long Period ◽  
Inositol 1,4,5 Trisphosphate ◽  
S Period

The properties of inositol 1,4,5-trisphosphate (IP3)-dependent intracellular calcium oscillations in pancreatic acinar cells depend crucially on the agonist used to stimulate them. Acetylcholine or carbachol (CCh) cause high-frequency (10–12-s period) calcium oscillations that are superimposed on a raised baseline, while cholecystokinin (CCK) causes long-period (&gt;100-s period) baseline spiking. We show that physiological concentrations of CCK induce rapid phosphorylation of the IP3 receptor, which is not true of physiological concentrations of CCh. Based on this and other experimental data, we construct a mathematical model of agonist-specific intracellular calcium oscillations in pancreatic acinar cells. Model simulations agree with previous experimental work on the rates of activation and inactivation of the IP3 receptor by calcium (DuFour, J.-F., I.M. Arias, and T.J. Turner. 1997. J. Biol. Chem. 272:2675–2681), and reproduce both short-period, raised baseline oscillations, and long-period baseline spiking. The steady state open probability curve of the model IP3 receptor is an increasing function of calcium concentration, as found for type-III IP3 receptors by Hagar et al. (Hagar, R.E., A.D. Burgstahler, M.H. Nathanson, and B.E. Ehrlich. 1998. Nature. 396:81–84). We use the model to predict the effect of the removal of external calcium, and this prediction is confirmed experimentally. We also predict that, for type-III IP3 receptors, the steady state open probability curve will shift to lower calcium concentrations as the background IP3 concentration increases. We conclude that the differences between CCh- and CCK-induced calcium oscillations in pancreatic acinar cells can be explained by two principal mechanisms: (a) CCK causes more phosphorylation of the IP3 receptor than does CCh, and the phosphorylated receptor cannot pass calcium current; and (b) the rate of calcium ATPase pumping and the rate of calcium influx from the outside the cell are greater in the presence of CCh than in the presence of CCK.

Nitric oxide inhibits calcium release from sarcoplasmic reticulum of porcine tracheal smooth muscle cells

1997 ◽  
Vol 272 (1) ◽  
pp. L1-L7 ◽  
Author(s):  
M. S. Kannan ◽  
Y. S. Prakash ◽  
D. E. Johnson ◽  
G. C. Sieck
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Sarcoplasmic Reticulum ◽  
Calcium Release ◽  
Ryanodine Receptors ◽  
Tracheal Smooth Muscle ◽  
Nitric Oxide Donor ◽  
Ip3 Receptors ◽  
Video Fluorescence Microscopy ◽  
Inositol 1,4,5 Trisphosphate

In the present study, effects of the nitric oxide donor, S-nitroso-N-acetylpenicillamine (SNAP), on sarcoplasmic reticulum (SR) Ca2+ release were examined in freshly dissociated porcine tracheal smooth muscle (TSM) cells. Fura 2-loaded TSM cells were imaged using video fluorescence microscopy. SR Ca2+ release was induced by acetylcholine (ACh), which acts principally through inositol 1,4,5-trisphosphate (IP3) receptors, and by caffeine, which acts principally through ryanodine receptors (RyR). SNAP inhibited ACh-induced SR Ca2+ release at both 0 and 2.5 mM extracellular Ca2+. Degraded SNAP had no effect on ACh-induced SR Ca2+ release. SNAP also inhibited caffeine-induced SR Ca2+ release. ACh-induced Ca2+ influx was not affected by SNAP when SR reloading was blocked by thapsigargin. SNAP also did not affect SR Ca2+ reuptake. The membrane-permeant analogue of guanosine 3',5'-cyclic monophosphate (cGMP), 8-bromo-cGMP, mimicked the effects of SNAP. These results suggest that, in porcine TSM cells, SNAP reduces the intracellular Ca2+ response to ACh and caffeine by inhibiting SR Ca2+ release through both IP3 and RyR, but not by inhibiting influx or repletion of the SR Ca2+ stores. These effects are likely mediated via cGMP-dependent mechanisms.

Calcium release by cholecystokinin analogue OPE is IP3 dependent in single rat pancreatic acinar cells

1994 ◽  
Vol 267 (1) ◽  
pp. C220-C228 ◽  
Author(s):  
H. Y. Gaisano ◽  
D. Wong ◽  
L. Sheu ◽  
J. K. Foskett
Keyword(s):  
Molecular Weight ◽  
Low Molecular Weight Heparin ◽  
Calcium Release ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Low Molecular Weight ◽  
Ip3 Receptor ◽  
Intact Cells ◽  
Inositol 1,4,5 Trisphosphate ◽  
Low Levels

Cholecystokinin (CCK) and carbachol raise intracellular Ca2+ concentration ([Ca2+]i) in pancreatic acinar cells by elevating inositol 1,4,5-trisphosphate (IP3). CCK analogues JMV-180 and OPE stimulate fully efficacious enzyme secretion and [Ca2+]i oscillations but release Ca2+ from intracellular stores by apparently IP3-independent mechanisms in permeabilized acinar cells. In the present study, we investigated whether OPE mobilizes Ca2+ from IP3-sensitive Ca2+ stores and whether IP3 mediates such responses in single intact cells. OPE and JMV-180 similarly elevated IP3 to low levels compared with those elicited by 10 nM CCK. Depletion of IP3-sensitive stores by elevation of intracellular IP3 using carbachol, microinjection of a nonmetabolizable IP3 analogue, or exposure to thapsigargin, in the absence of extracellular Ca2+, depleted the same Ca2+ stores that were sensitive to OPE. In converse experiments, OPE depleted carbachol- or thapsigargin-sensitive stores, indicating that carbachol-, thapsigargin-, IP3-, and OPE-sensitive Ca2+ stores overlap completely and that stores mobilized by OPE are IP3 sensitive. To determine whether IP3 mediates responses to OPE, cells were microinjected with low-molecular-weight heparin, a competitive inhibited the rise of [Ca2+]i in response to carbachol, OPE, or JMV-180, whereas de-N-sulfated heparin, an inactive heparin, was without effect. These results indicate that CCK analogues release Ca2+ from IP3-sensitive Ca2+ stores by mechanisms involving the IP3 receptor.

scholarly journals 80K-H Interacts with Inositol 1,4,5-Trisphosphate (IP3) Receptors and Regulates IP3-induced Calcium Release Activity

2008 ◽  
Vol 284 (1) ◽  
pp. 372-380 ◽  
Author(s):  
Katsuhiro Kawaai ◽  
Chihiro Hisatsune ◽  
Yukiko Kuroda ◽  
Akihiro Mizutani ◽  
Tomoko Tashiro ◽  
...  
Keyword(s):  
Calcium Release ◽  
Ip3 Receptors ◽  
Inositol 1,4,5 Trisphosphate

scholarly journals Role of ERO1-α–mediated stimulation of inositol 1,4,5-triphosphate receptor activity in endoplasmic reticulum stress–induced apoptosis

2009 ◽  
Vol 186 (6) ◽  
pp. 783-792 ◽  
Author(s):  
Gang Li ◽  
Marco Mongillo ◽  
King-Tung Chin ◽  
Heather Harding ◽  
David Ron ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Calcium Release ◽  
Loss Of Function ◽  
Ip3 Receptor ◽  
Calcium Dependent ◽  
Insulin Resistant ◽  
Stressed Cells ◽  
Induced Apoptosis

Endoplasmic reticulum (ER) stress–induced apoptosis is involved in many diseases, but the mechanisms linking ER stress to apoptosis are incompletely understood. Based on roles for C/EPB homologous protein (CHOP) and ER calcium release in apoptosis, we hypothesized that apoptosis involves the activation of inositol 1,4,5-triphosphate (IP3) receptor (IP3R) via CHOP-induced ERO1-α (ER oxidase 1 α). In ER-stressed cells, ERO1-α is induced by CHOP, and small interfering RNA (siRNA) knockdown of ERO1-α suppresses apoptosis. IP3-induced calcium release (IICR) is increased during ER stress, and this response is blocked by siRNA-mediated silencing of ERO1-α or IP3R1 and by loss-of-function mutations in Ero1a or Chop. Reconstitution of ERO1-α in Chop−/− macrophages restores ER stress–induced IICR and apoptosis. In vivo, macrophages from wild-type mice but not Chop−/− mice have elevated IICR when the animals are challenged with the ER stressor tunicamycin. Macrophages from insulin-resistant ob/ob mice, another model of ER stress, also have elevated IICR. These data shed new light on how the CHOP pathway of apoptosis triggers calcium-dependent apoptosis through an ERO1-α–IP3R pathway.

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