Oncogenic potential of TASK3 (Kcnk9) depends on K+ channel function. Proc Natl Acad Sci USA

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Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 07/2003; 100(13):7803-7. DOI: 10.1073/pnas.1232448100
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TASK3 gene (Kcnk9) is amplified and overexpressed in several types of human carcinomas. In this report, we demonstrate that a point mutation (G95E) within the consensus K+ filter of TASK3 not only abolished TASK3 potassium channel activity but also abrogated its oncogenic functions, including proliferation in low serum, resistance to apoptosis, and promotion of tumor growth. Furthermore, we provide evidence that TASK3G95E is a dominant-negative mutation, because coexpression of the wild-type and the mutant TASK3 resulted in inhibition of K+ current of wild-type TASK3 and its tumorigenicity in nude mice. These results establish a direct link between the potassium channel activity of TASK3 and its oncogenic functions and imply that blockers for this potassium channel may have therapeutic potential for the treatment of cancers.

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Available from: Timothy Hoey, Oct 04, 2015
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    ABSTRACT: K+ channels participate in many biological functions from ion homeostasis to generation and modulation of the electrical membrane potential. They are involved in a large variety of diseases. In the human genome, 15 genes code for K+ channels with two pore-domains (K2P). These channels form dimers of pore-forming subunits that produce background conductances finely regulated by a range of natural and chemical effectors, including signaling lipids, temperature, pressure, pH, antidepressants and volatile anesthetics. Since the cloning of TWIK1, the prototypical member of this family, a lot of work has been carried out about their structure and biology. These studies are still in progress, but data gathered so far show that K2P channels are central players in many processes including ion homeostasis, hormone secretion, cell development and excitability. A growing number of studies underline their implication in physiopathological mechanisms such as vascular and pulmonary hypertension, cardiac arrhythmias, nociception, neuroprotection and depression. This review gives a synthetic view of the most noticeable features of these channels.This article is protected by copyright. All rights reserved
    The Journal of Physiology 12/2014; 593(12). DOI:10.1113/jphysiol.2014.287268 · 5.04 Impact Factor
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    • "Similarly, targeting the big conductance K+ channel with the inhibitor tetraethyl ammonium attenuates cisplatin-induced apoptosis in type I spiral ligament fibrocytes [43] and mouse neocortical neurons [44]. The TASK3 gene (Kcnk9) is overexpressed in several types of human carcinomas which has been associated with resistance towards apoptosis [45]. This is in contrast to what is seen in different glioma cell lines where application of the TASK3 channel opener isoflurane significantly reduces cell survival and the TASK channel blockers bupivacaine and spermine completely reverses this effect [46]. "
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    ABSTRACT: Multi-drug resistance (MDR) to chemotherapy is the major challenge in the treatment of cancer. MDR can develop by numerous mechanisms including decreased drug uptake, increased drug efflux and the failure to undergo drug-induced apoptosis. Evasion of drug-induced apoptosis through modulation of ion transporters is the main focus of this paper and we demonstrate how pro-apoptotic ion channels are downregulated, while anti-apoptotic ion transporters are upregulated in MDR. We also discuss whether upregulation of ion transport proteins that are important for proliferation contribute to MDR. Finally, we discuss the possibility that the development of MDR involves sequential and localized upregulation of ion channels involved in proliferation and migration and a concomitant global and persistent downregulation of ion channels involved in apoptosis.
    Philosophical Transactions of The Royal Society B Biological Sciences 03/2014; 369(1638):20130109. DOI:10.1098/rstb.2013.0109 · 7.06 Impact Factor
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    • "TASK3 channels also play an important role in the migration of cortical pyramidal neurons during development (Bando et al., 2012), and TASK3 knockout mice show abnormalities in certain cognitive functions (Linden et al., 2007). TASK3 channels are proposed to play a role in various pathologic conditions such as epilepsy (Kananura et al., 2002), cancer (Mu et al., 2003; Pei et al., 2003), ischemia (Ehling et al., 2010), idiopathic hyperaldosteronism, particularly in neonates (Davies et al., 2008; Bandulik et al., 2013), and low renin essential hypertension (Guagliardo et al., 2012; Penton et al., 2012). TASK3 channels are the only K2P channels known to be genetically imprinted, in that they are expressed only from the maternal allele (Luedi et al., 2007). "
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    ABSTRACT: TASK3 potassium channels are members of the two pore domain potassium channel family. They are responsible for background leak potassium currents found in many cell types. TASK3 channels are genetically imprinted and a mutation in TASK3 (G236R) is responsible for a maternally transmitted developmental disorder, Birk Barel mental retardation dysmorphism syndrome. This syndrome may arise from a neuronal migration defect during development caused by dysfunctional TASK3 channels. Through the use of whole-cell electrophysiological recordings, we have found that although G236R mutated TASK3 channels give rise to a functional current, this current is significantly smaller in an outward direction when compared to wild type (WT) TASK3 channels. In contrast to WT TASK3 channels, the current is inwardly-rectifying. Furthermore, the current through mutated channels is differentially sensitive to a number of regulators such as extracellular acidification, extracellular zinc and activation of Gαq-coupled muscarinic (M3) receptors compared with WT TASK3 channels. The reduced outward current through mutated TASK3_G236R channels can be overcome, at least in part, by both a gain of function additional mutation of TASK3 channels (A237T) or by application of the non-steroidal anti-inflammatory drug, flufenamic acid. Flufenamic acid produces a significantly greater enhancement of current through mutated channels than through WT TASK3 channels. We propose that pharmacological enhancement of mutated TASK3 channel current during development may, therefore, provide a potentially useful therapeutic strategy in the treatment of Birk Barel syndrome.
    Molecular pharmacology 12/2013; DOI:10.1124/mol.113.090530 · 4.13 Impact Factor
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