LY294002, but not wortmannin, increases intracellular calcium and inhibits calcium transients in bovine and human airway smooth muscle cells

Ethier, Michael F.; Madison, J. Mark

doi:10.1016/s0143-4160(02)00111-2

Cited by 36 publications

(34 citation statements)

References 27 publications

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“…Neither wortmannin nor deguelin alone had effects on basal [Ca 2ϩ ] i , and, by themselves, these antagonists had no effect on S2/S1 ratios. LY294002 (50 M) did not antagonize IL-4 effects, but as previously reported, it did have a nonspecific inhibitory effect on transients by itself (Ethier and Madison, 2002).…”

Section: Effects Of Il-4 Alone On [supporting

confidence: 66%

“…However, it had nonspecific effects on calcium transients by itself, making it poorly suitable for these experiments. Although the mechanism of this nonspecific effect is not known, a previous study showed that LY294002 mobilizes intracellular calcium stores in airway smooth muscle by mechanisms independent of PI3K, IP 3 R, and PLC (Ethier and Madison, 2002). Evidence in other cell types also suggests that LY294002 has nonspecific effects on calcium regulation (Pasquet et al, 1999;Straube and Parekh, 2001;Warashina, 2001).…”

Section: Discussionmentioning

confidence: 99%

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Mechanisms of Interleukin-4 Effects on Calcium Signaling in Airway Smooth Muscle Cells

Ethier¹,

Cappelluti²,

Madison³

2005

J Pharmacol Exp Ther

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In airway smooth muscle cells, interleukin (IL)-4 inhibited both carbachol-and caffeine-induced calcium mobilization from the sarcoplasmic reticulum (SR). Because of the known signaling pathways for IL-4 and importance of calcium uptake in maintaining SR calcium stores shared by agonists and caffeine, it was hypothesized that this rapid inhibitory effect might depend on phosphatidylinositol 3-kinase (PI3K) and on inhibition of calcium uptake by the SR. Enzyme-dispersed bovine trachealis cells were loaded with Fura-2/acetoxymethyl ester, and changes in cytosolic calcium were imaged in single cells. Cells were pretreated with inhibitors of PI3K, either wortmannin (100 nM), LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one] (50 M), or deguelin (100 nM). Calcium transients in response to carbachol (10 M) were significantly decreased to 0.34 Ϯ 0.10 of control after 20-min treatment with IL-4 but were 1.10 Ϯ 0.26 and 1.08 Ϯ 0.23 when wortmannin or deguelin, respectively, was added along with IL-4. LY294002 alone had nonspecific effects on transients. In other experiments, cyclopiazonic acid (CPA) (5 M), an inhibitor of SR calcium uptake, decreased carbachol-stimulated transients within 4 min to 0.83 Ϯ 0.08 of control (n ϭ 6). However, for cells treated with IL-4 (50 ng/ml) plus CPA, transients decreased significantly more, to only 0.51 Ϯ 0.05 (n ϭ 6; p Ͻ 0.05). Longer exposures to IL-4 and a higher concentration of CPA (30 M) gave similar results. It was concluded that IL-4 did not inhibit transients in the presence of PI3K antagonists but that it did in the presence of CPA. This suggested that IL-4 inhibited calcium transients by mechanisms dependent upon a wortmannin-sensitive PI3K but not by inhibition of calcium uptake into the SR.T helper-2 cytokines, including IL-4 and the closely related cytokine IL-13, have important and complex effects on airway inflammation and airway cells (Brusselle et al

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Section: Effects Of Il-4 Alone On [supporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Mechanisms of Interleukin-4 Effects on Calcium Signaling in Airway Smooth Muscle Cells

Ethier¹,

Cappelluti²,

Madison³

2005

J Pharmacol Exp Ther

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“…LY29 has been shown to act as a direct blocker of L-type Ca 2+ channel with IC50 of 20 µM (Welling et al, 2005). LY has also been shown to prevent [Ca 2+ ] i increases triggered by thapsigargin, carbachol, caffeine and histamine in a PI3K independent manner (Ethier and Madison, 2002). Although how CT causes an elevation of [Ca 2+ ] i in cardiomyocytes remains to be determined, an earlier study has reported a stimulatory effect of glucocorticoids on voltage-gated calcium channels (Fomina et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

“…TEA at mM concentration has been commonly used to inhibit potassium channel in various experimental models. In addition to blocking potassium channel, LY29 has also been shown to alter intracellular calcium levels by regulating calcium channel (Straube and Parekh, 2001;Ethier and Madison, 2002;Welling et al, 2005). The effect of nimodipine, a voltage-gated calcium channel blocker, was examined on CT-induced COX-2 induction.…”

Section: Tea and Nomidipine Inhibit Cox-2 Inductionmentioning

confidence: 99%

LY294002 inhibits glucocorticoid-induced COX-2 gene expression in cardiomyocytes through a phosphatidylinositol 3 kinase-independent mechanism

Sun

Шевелева

et al. 2008

Toxicology and Applied Pharmacology

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Glucocorticoids induce COX-2 expression in rat cardiomyocytes. While investigating whether phosphatidylinositol 3 kinase (PI3K) plays a role in corticosterone (CT) induced COX-2, we found that LY294002 (LY29) but not wortmannin (WM) attenuates CT from inducing COX-2 gene expression. Expression of a dominant-negative mutant of p85 subunit of PI3K failed to inhibit CT from inducing COX-2 expression. CT did not activate PI3K/AKT signaling pathway whereas LY29 and WM decreased the activity of PI3K. LY303511 (LY30), a structural analogue and a negative control for PI3K inhibitory activity of LY29, also suppressed COX-2 induction. These data suggest PI3K independent mechanisms in regulating CT induced COX-2 expression. LY29 and LY30 do not inhibit glucocorticoid receptor transactivity. Both compounds have been reported to inhibit Casein Kinase 2 activity and modulate potassium and calcium levels independent of PI3K, while LY29 has been reported to inhibit mammalian Target of Rapamycin (mTOR), DNA-dependent Protein Kinase (DNA-PK). Inhibitor of Casein Kinase 2 (CK2), mTOR or DNA-PK failed to prevent CT from inducing COX-2 expression. Tetraethylammonium (TEA), a potassium channel blocker, and nimodipine, a calcium channel blocker, both attenuated CT from inducing COX-2 gene expression. CT was found to increase intracellular Ca 2+ concentration, which can be inhibited by LY29, TEA or nimodipine. These data suggest a possible role of calcium instead of PI3K in CT induced COX-2 expression in cardiomyocytes.

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“…In addition, studies also have shown that LY294002 activated autophagy by inhibiting the class I PI3K signaling pathway [83] . LY294002 increased intracellular calcium, at least in part, by mobilizing intracellular calcium stores and inhibiting calcium transients [84] . Therefore, experiments where calcium is relevant should avoid using LY294002.…”

Section: Pi3k Inhibitorsmentioning

confidence: 99%

Application and interpretation of current autophagy inhibitors and activators

et al. 2013

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Autophagy is the major intracellular degradation system, by which cytoplasmic materials are delivered to and degraded in the lysosome. As a quality control mechanism for cytoplasmic proteins and organelles, autophagy plays important roles in a variety of human diseases, including neurodegenerative diseases, cancer, cardiovascular disease, diabetes and infectious and inflammatory diseases. The discovery of ATG genes and the dissection of the signaling pathways involved in regulating autophagy have greatly enriched our knowledge on the occurrence and development of this lysosomal degradation pathway. In addition to its role in degradation, autophagy may also promote a type of programmed cell death that is different from apoptosis, termed type II programmed cell death. Owing to the dual roles of autophagy in cell death and the specificity of diseases, the exact mechanisms of autophagy in various diseases require more investigation. The application of autophagy inhibitors and activators will help us understand the regulation of autophagy in human diseases, and provide insight into the use of autophagy-targeted drugs. In this review, we summarize the latest research on autophagy inhibitors and activators and discuss the possibility of their application in human disease therapy.

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LY294002, but not wortmannin, increases intracellular calcium and inhibits calcium transients in bovine and human airway smooth muscle cells

Cited by 36 publications

References 27 publications

Mechanisms of Interleukin-4 Effects on Calcium Signaling in Airway Smooth Muscle Cells

Mechanisms of Interleukin-4 Effects on Calcium Signaling in Airway Smooth Muscle Cells

LY294002 inhibits glucocorticoid-induced COX-2 gene expression in cardiomyocytes through a phosphatidylinositol 3 kinase-independent mechanism

Application and interpretation of current autophagy inhibitors and activators

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