1,721,073 research outputs found
Mitochondrial ion channels as oncological targets
No full textMitochondria, the key bioenergetic intracellular organelles, harbor a number of proteins with proven or hypothetical ion channel functions. Growing evidence points to the important contribution of these channels to the regulation of mitochondrial function, such as ion homeostasis imbalances profoundly affecting energy transducing processes, reactive oxygen species production and mitochondrial integrity. Given the central role of mitochondria in apoptosis, their ion channels with the potential to compromise mitochondrial function have become promising targets for the treatment of malignancies. Importantly, in vivo evidence demonstrates the involvement of the proton-transporting uncoupling protein, a mitochondrial potassium channel, the outer membrane located porin and the permeability transition pore in tumor progression/control. In this review, we focus on mitochondrial channels that have been assigned a definite role in cell death regulation and possess clear oncological relevance. Overall, based on in vivo and in vitro genetic and pharmacological evidence, mitochondrial ion channels are emerging as promising targets for cancer treatment.Oncogene advance online publication, 27 January 2014; doi:10.1038/onc.2013.578
Perioperative disturbances: H2O and electrolyte imbalances - Cytosolic pH in regulation of cell proliferation and apoptotic cell death
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Ruolo dell'endotelina e dell'endothelum-derived relaxing factor nella microcircolazione renale
No full textInhibitory effects of oxidants on n-type K+ channels in T lymphocytes and Xenopus oocytes (Szabo è corresponding author)
No full textReactive oxygen species (ROS) appear to be involved in Fas-induced programmed cell death. We have previously demonstrated a tyrosine-kinase-dependent inhibition of the n-type K+ channels (Kn) by Fas stimulation. Thus, the effect of hydrogen peroxide (H2O2) on the function of Kn was examined using the patch-clamp technique. Incubation of Jurkat human T lymphocytes with 100 microM H2O2 resulted in a 46 +/- 5% inhibition of the macroscopic whole-cell current. Experiments performed at the single-channel level using the cell-attached configuration revealed that the probability of the channel being open diminished upon incubation in H2O2. The effect was not dependent on src-like kinases, since H2O2 did not trigger tyrosine phosphorylation of the Kn channel protein and herbimycin A did not prevent channel inhibition. Kv1.3 channels underly the Kn of T lymphocytes and were expressed in Xenopus oocytes and subjected to electrophysiological analysis by the two-electrode voltage-clamp technique. Application of 1 mM H2O2 and 500 microM t-BOOH (tert, butylhydroperoxide) resulted in a marked inhibition of the K+ current within 20 min. Both the membrane-permeable thiol-group oxidizing agent DTNP [2,2'-dithiobis-(5-nitropyridine)] and the membrane-impermeable DTNB [5,5'-Dithiobis-(2-nitrobenzoic acid)] (50 microM) inhibited Kv1.3 channels, suggesting that extracellular domains of Kv1.3 are affected. These results point to a direct modulation of Kn by various oxidative agents
Ceramide induced inhibition of T lymphocyte voltage-gated potassium channel is mediated by tyrosine kinases
No full textThe n-type K+ channel (n-K+, Kv1.3) in lymphocytes has been recently implicated in the regulation of Fas-induced programmed cell death. Here, we demonstrate that ceramide, a lipid metabolite synthesized upon Fas receptor ligation, inhibits n-K+ channel activity and induces a tyrosine phosphorylation of the Kv1.3 protein in Jurkat T lymphocytes. Tyrosine phosphorylation of the n-K+ channel correlated with an activation of the Src-like tyrosine kinase p56lck upon cellular treatment with the ceramide analog C6-ceramide. Because genetic deficiency of p56lck or inhibition of Src-like tyrosine kinases by herbimycin A prevented ceramide-mediated n-K+ channel inhibition and tyrosine phosphorylation, we propose a ceramide-initiated activation of p56lck resulting in tyrosine phosphorylation and inhibition of the n-K+ channel protein
Actinomycin D induced apoptosis involves the potassium channel Kv1.3
No full textSeveral cytostatic agents are known to induce apoptosis in T-leukemic cells. Although a variety of studies show the central role of
apoptosis in cytostatic drug-induced cell death, many molecular details require definition. Here, we demonstrate that cells genetically
deficient for the potassium channel Kv1.3 are resistant to apoptosis initiated by the cytostatic drug actinomycin D. Retransfection
of Kv1.3 restores sensitivity of the cells to actinomycin D. Cells lacking Kv1.3 fail to respond to actinomycin D with
DNA fragmentation, release of cytochrome c, and loss of mitochondrial membrane potential (DWm), while cells functionally expressing
Kv1.3 rapidly undergo those changes indicative for apoptosis. The data indicate a central role of the ion channel Kv1.3 in
actinomycin D-triggered apoptosis. 2002 Elsevier Science (USA). All rights reserved
Physiology of mitochondrial potassium channels
No full textThe inner membrane of the ATP-producing organelles of endosymbiotic origin, mitochondria, has long been considered to be poorly permeable to cations and anions, since the strict control of inner mitochondrial membrane permeability is crucial for efficient ATP synthesis. Over the past 30 years, however, it has become clear that various ion channels-along with antiporters and uniporters-are present in the mitochondrial inner membrane, although at rather low abundance. These channels are important for energy supply, and some are a decisive factor in determining whether a cell lives or dies. Their electrophysiological and pharmacological characterisations have contributed importantly to the ongoing elucidation of their pathophysiological roles. This review gives an overview of recent advances in our understanding of the functions of the mitochondrial potassium channels identified so far. Open issues concerning the possible molecular entities giving rise to the observed activities and channel protein targeting to mitochondria are also discussed
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