Stimulation of the phosphoinositide signalling system as a possible mechanism for glucocorticoid action in blood pressure control

Steiner, Albert; Vogt, Esther; Locher, Rudolf; Vetter, W

doi:10.1097/00004872-198812040-00114

Cited by 39 publications

(17 citation statements)

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“…Recent evidence suggests, however, that steroid hormones may also exert shortterm, nongenomic effects [for reviews see Wehling, 1994;Brann et al, 19951. Indeed, rapid effects have been reported for almost every steroid [Wehling, 19941, including cortisol [Hua and Chen, 1989;Ffrench-Mullen et al, 1994;Steiner et al, 1988;Borski et al, 19911, and other glucocorticoids [Edwardson and Bennett, 1974;Hall, 19821. The finding that dexamethasone binds to plasma membrane-enriched liver fractions [Qelle et al, 19881 further supports the notion that glucocorticoids may affect cellular pathways independently of their cytoplasmic receptors.…”

Section: Discussionmentioning

confidence: 99%

Dexamethasone alters rapidly actin polymerization dynamics in human endometrial cells: Evidence for nongenomic actions involving cAMP turnover

et al. 1996

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Glucocorticoids, in addition to their well characterized effects on the genome, may affect cell function in a manner not involving genomic pathways. The mechanisms by which the latter is achieved are not yet clear. A possible means for this action may involve the actin cytoskeleton, since the dynamic equilibrium of actin polymerization changes rapidly following exposure to several stimuli, including hormones. The aim of the present work was to find out if glucocorticoids exert rapid, nongenomic effects on actin polymerization in Ishikawa human endometrial cells, which represent a well characterized in vitro cell model expressing functional glucocorticoid receptors. Short term exposure of the cells to the synthetic glucocorticoid dexamethasone resulted in an overall decrease of the G/total-actin ratio in a time- and dose-dependent manner. Specifically, in untreated Ishikawa cells the G/total-actin ratio was 0.48 +/- 0.01 (n = 26). It became 0.35 +/- 0.01 (n = 13, P < 0.01) following exposure to 10(-7) M dexamethasone for 15 min. This was induced by a significant decrease of the cellular G-actin level, without affecting the total actin content, indicating a rapid actin polymerization. This conclusion was fully confirmed by direct fluorimetry measurements, that showed a significant increase of the F-actin content by 44% (n = 6, P < 0.001) in cells treated with dexamethasone (10(-7)M, 15 min). The rapid dexamethasone-induced alterations of the state of actin polymerization were further supported by fluorescence microscopy. The latter studies showed that the microfilaments of cells pretreated with 10(-7)M dexamethasone for 15 min were more resistant to various concentrations of the antimicrofilament drug cytochalasin B, compared to untreated cells, implying microfilament stabilization. The action of dexamethasone on actin polymerization seems to be mediated via specific glucocorticoid binding sites, since the addition of the glucocorticoid antagonist RU486 completely abolished its effect. Moreover, it appears to act via non-transcriptional pathways, since actinomycin D did not block the dexamethasone-induced actin polymerization. In addition, cell treatment with 10(-7)M dexamethasone for 15 min fully reversed the forskolin-, but not the 8-bromo-cAMP-induced actin depolymerization. In line with these findings, the cAMP content of Ishikawa cells was decreased by 29.2% after a 15 min treatment with 10(-7)M dexamethasone (n = 4, P < 0.01). In conclusion, our results showed that dexamethasone induces rapid, time-, and dose-dependent changes in actin polymerization dynamics in Ishikawa cells. This action seems to be mediated via cAMP, involving probably nongenomic pathways. The above findings offer new perspectives for the understanding of the early cellular responses to glucocorticoids.

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Section: Discussionmentioning

confidence: 99%

Dexamethasone alters rapidly actin polymerization dynamics in human endometrial cells: Evidence for nongenomic actions involving cAMP turnover

et al. 1996

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“…However, it should be noted that this concept does not exclude the possibility of indirect downstream transcriptional modulation secondary to the initiated signaling pathways. Corticosteroids alter amphibian behavior and increase inositol trisphosphate in vascular smooth muscle cells within minutes of administration [53,54]. In mice the antianaphylactic effect of high-dose corticosteroids occurs acutely and is unaltered by the transcriptional inhibitor actinomycin D [55].…”

Section: Rapid Nontranscriptional Effects Of Grmentioning

confidence: 99%

Nontranscriptional actions of the glucocorticoid receptor

Limbourg

Liao

2003

J Mol Med

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Many cellular responses to corticosteroids involve the transcriptional modulation of target genes by a prototypical nuclear receptor, the glucocorticoid receptor (GR). In the classic model of steroid hormone action GR acts as ligand-dependent transcription factor by either activating or repressing gene expression through direct interactions with DNA or other transcription factors. Recent evidence suggests an important role for nontranscriptional effects of GR in the vascular system. The nontranscriptional actions of GR involve the rapid activation of protein kinases, such as phosphatidylinositol-3 kinase and Akt, leading to the activation of endothelial nitric oxide synthase. This novel pathway of steroid hormone action protects against ischemic injury by augmenting blood flow and decreasing vascular inflammation.

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“…Such effects have been suggested for almost every steroid [Edwardson and Bennett, 1974;Hall, 1982;Steiner et al, 1988;Hua and Chen, 1989;Borski et al, 1991;Ffrench-Mullen et al, 1994]. However, the mechanisms by which these nongenomic effects are mediated have not yet been clarified.…”

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confidence: 99%

Dexamethasone induces rapid actin assembly in human endometrial cells without affecting its synthesis

et al. 1997

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Dexamethasone exerts a stimulatory effect of rapid-onset on the polymerization of actin. This has been documented in human endometrial adenocarcinoma Ishikawa cells, resulting in an acute, dose-dependent decrease in the G/total-actin ratio. In the present study we completely characterized this fast and apparently nongenomic effect of dexamethasone on actin assembly. We followed the morphological alterations of actin cytoskeleton and measured the time-dependent dynamics of actin polymerization both by ruling out any changes of total actin in the cells and by measuring its transcript. Rapid changes in actin polymerization were accurately measured using a highly sensitive and quantitative rhodamine-phalloidin fluorimetric assay. Ishikawa cells, exposed to 0.1 microM dexamethasone for various time periods up to 24 h, showed a highly significant, rapid, and transient increase in the polymerization of actin starting within 15 min of dexamethasone exposure and lasting 2 h. Treated cells showed a significant (1.79-fold) enhancement of the fluorescent signal compared to untreated cells at 15 min. This value decreased continuously in a time-dependent manner, reaching control levels after 120 min and remained so for the next 24 h. Confocal laser scanning microscopy studies confirmed these findings. Intensive coloration of microfilaments over several scanning sections suggested an enhanced degree of actin polymerization in cells preincubated for 15 min with 0.1 microM dexamethasone. Moreover, actin filaments were more resistant to cytochalasin B. Additionally, quantitative immunoblot analysis showed that the content of total cellular actin remained the same during this period, suggesting that the biosynthesis of actin was unaffected. Northern blot analysis showed that the concentration of the actin transcript was also unaffected. Our data suggest that glucocorticoids induce a fast and self-limited polymerization of actin in human endometrial cells without affecting its synthesis. These findings strengthen the hypothesis that glucocorticoids exert rapid, nongenomic cellular effects and that the actin-based cytoskeleton is an integral part of this pathway, playing an essential role in receiving and mediating steroid signals for the modulation of cellular responses.

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Stimulation of the phosphoinositide signalling system as a possible mechanism for glucocorticoid action in blood pressure control

Cited by 39 publications

References 0 publications

Dexamethasone alters rapidly actin polymerization dynamics in human endometrial cells: Evidence for nongenomic actions involving cAMP turnover

Dexamethasone alters rapidly actin polymerization dynamics in human endometrial cells: Evidence for nongenomic actions involving cAMP turnover

Nontranscriptional actions of the glucocorticoid receptor

Dexamethasone induces rapid actin assembly in human endometrial cells without affecting its synthesis

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