Characterization of the molecular interaction between caveolin-1 and the P2X receptors 4 and 7 in E10 mouse lung alveolar epithelial cells

Barth, Kathrin; Weinhold, Karina; Guenther, Andreas; Linge, Annett; Gereke, Marcus; Kasper, Michael

doi:10.1016/j.biocel.2008.03.001

Cited by 30 publications

(39 citation statements)

References 29 publications

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“…We have previously shown that the purinergic receptor P2X7 mediates the rapid effects of statins on Akt activation. P2X7, along with P2X4, is expressed in lung epithelial cells, and partly associates with lipid rafts (23,24); these receptors have been demonstrated to form functional heterotrimers (25,26). Moreover, caveolin-1 was shown to interact with P2X7 and positively regulate its expression (23).…”

Section: Resultsmentioning

confidence: 99%

Statins exhibit anticancer effects through modifications of the pAkt signaling pathway

Miraglia

Högberg²,

Stenius

2011

Int J Oncol

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Abstract. Statins are cholesterol lowering drugs that exhibit antitumor effects in several in vitro and in vivo models, and epidemiological studies indicate that statins prevent cancer. However, the molecular mechanism underlying the effects of statins still needs to be elucidated. We previously demonstrated that single doses of different statins rapidly affect Akt signaling via the purinergic receptor P2X7. In particular, statins down-regulated nuclear pAkt. Here, we report that long-term treatment of A549 cells with high concentrations of statins (15-75 µM) selects cell sub-populations exhibiting altered P2X receptor expression, signs of increased PTEN activity, enhanced PHLPP2, decreased PI3K p110β and inhibited downstream pAkt signaling. Furthermore, the nuclear accumulation of pAkt in response to insulin was inhibited in selected cells. Statin-selected cells displayed reduced proliferation rate and were more vulnerable to etoposide-and 5-fluorouracil-elicited cytotoxic effects. The stability of a selected phenotype (50 µM) was tested for three weeks in the absence of statins. This resulted in a reversal of some, but not all alterations. Importantly, the truncated nuclear insulin response was retained. We conclude that long-term treatment with high doses of statins selects cells exhibiting stable alterations in insulin-Akt signaling and which are vulnerable to DNA damage. Our studies strengthen the hypothesis that an altered Akt signaling has a role in chemopreventive effects of statins.

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Section: Resultsmentioning

confidence: 99%

Statins exhibit anticancer effects through modifications of the pAkt signaling pathway

Miraglia

Högberg²,

Stenius

2011

Int J Oncol

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“…P2X7 receptors were found to be expressed on the ATIlike E10 cell line (Barth et al, 2007). There seems to be an interaction between P2X7 receptor protein and Caveolin-1 in lipid rafts in E10 cells (Barth et al, 2007(Barth et al, , 2008. Reverse transcription polymerase chain reaction (RT-PCR) studies revealed that NT-1 and A549 cells expressed P2X4, P2X5, and P2X6 receptor mRNA, whereas P2X7 receptors were detected only on NT-1 cells (Théâ tre et al, 2009).…”

Section: Lung and Intrapulmonary Airwaysmentioning

confidence: 99%

Purinergic Signaling in the Airways

Burnstock

Brouns²,

Adriaensen³

et al. 2012

Pharmacol Rev

174

158

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“…In this regard, it would be especially useful to understand the effects of danger signals on the main cell types that are infected by most pathogens, namely, mucosal epithelial cells. The expression and tissue distribution of purinergic receptors has been described for many kinds of epithelial cells (1,2,7,19,29,30,42,54,57,62,63,66), but functional characterization of these receptors in the context of infection of epithelial cells is lacking.…”

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confidence: 99%

Reversible Inhibition of Chlamydia trachomatis Infection in Epithelial Cells Due to Stimulation of P2X ₄ Receptors

et al. 2012

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Bacterial infections of the mucosal epithelium are a major cause of human disease. The prolonged presence of microbial pathogens stimulates inflammation of the local tissues, which leads to changes in the molecular composition of the extracellular milieu. A well-characterized molecule that is released to the extracellular milieu by stressed or infected cells is extracellular ATP and its ecto-enzymatic degradation products, which function as signaling molecules through ligation of purinergic receptors. There has been little information, however, on the effects of the extracellular metabolites on bacterial growth in inflamed tissues. Millimolar concentrations of ATP have been previously shown to inhibit irreversibly bacterial infection through ligation of P2X 7 receptors. We show here that the proinflammatory mediator, ATP, is released from Chlamydia trachomatis-infected epithelial cells. Moreover, further stimulation of the infected cells with micromolar extracellular ADP or ATP significantly impairs the growth of the bacteria, with a profile characteristic of the involvement of P2X 4 receptors. A specific role for P2X 4 was confirmed using cells overexpressing P2X 4 . The chlamydiae remain viable and return to normal growth kinetics after removal of the extracellular stimulus, similar to responses previously described for persistence of chlamydial infection. Danger signals comprise a varied group of extracellular molecules which indicate a potentially harmful physiological state and for which specific sensory mechanisms exist (38,40,51,55,56). Well-known danger signals include extracellular ATP, adenosine, uric acid crystals, the chromatin component HMGB1, and heat shock proteins. However, the level of danger posed elicits different cellular responses. For example, ATP is released from resting cells (nanomolar range) (5, 37), stressed and dying cells (micromolar range) (23), and physically compromised cells (millimolar range), although actual concentrations depend heavily on cell type and environment. Cells in the adjacent tissue must then decide whether to modify their own behavior in response to the extracellular signal, and whether to amplify the response by secreting other signaling molecules such as cytokines.The cells sense extracellular ATP and other nucleotides and nucleosides via a family of membrane receptors called purinergic receptors. These receptors are subdivided by function and homology into three classes: P2X are ligand-gated ion channels sensitive to ATP, P2Y are G-protein-coupled receptors stimulated by adenine and uracil nucleotides, and P1 receptors are also G protein coupled but are sensitive to adenosine (11,45). The tissue distribution and sensitivity to the ligands vary significantly within each family (12), such that slightly different concentrations of ligand can have different effects at a single cell type, and the same concentration of ligand can have contrasting effects on different cell types.While purinergic receptors have been best characterized in the central nervous system, the...

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Characterization of the molecular interaction between caveolin-1 and the P2X receptors 4 and 7 in E10 mouse lung alveolar epithelial cells

Cited by 30 publications

References 29 publications

Statins exhibit anticancer effects through modifications of the pAkt signaling pathway

Statins exhibit anticancer effects through modifications of the pAkt signaling pathway

Purinergic Signaling in the Airways

Reversible Inhibition of Chlamydia trachomatis Infection in Epithelial Cells Due to Stimulation of P2X ₄ Receptors

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Characterization of the molecular interaction between caveolin-1 and the P2X receptors 4 and 7 in E10 mouse lung alveolar epithelial cells

Cited by 30 publications

References 29 publications

Statins exhibit anticancer effects through modifications of the pAkt signaling pathway

Statins exhibit anticancer effects through modifications of the pAkt signaling pathway

Purinergic Signaling in the Airways

Reversible Inhibition of Chlamydia trachomatis Infection in Epithelial Cells Due to Stimulation of P2X 4 Receptors

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Product

Resources

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Reversible Inhibition of Chlamydia trachomatis Infection in Epithelial Cells Due to Stimulation of P2X ₄ Receptors