Mini-reviewEther à go-go potassium channels and cancer
Introduction
Ion channels are membrane proteins governing massive ion fluxes through the cells and participating in many and diverse physiological events such as excitability, contraction, cell cycle progression and metabolism [1] both in health and disease. Several channelopathies have been described and many of these proteins are therapeutic targets, highlighting the physiological relevance of ion channels [2]. In addition to leak channels, which are opened at resting membrane potential, there is a quite diverse group of channels needing a special signal to be gated. Gating signals vary from voltage and neurotransmitters to pH and temperature and are usually specific for a type of channel [3]. Several ion channels have been related to cell proliferation and/or cancer including calcium, chloride and sodium channels [4], [5], [6]; however, the ion channels most commonly related to cell proliferation and cancer are the potassium channels; actually some excellent general reviews on potassium channels and cell proliferation have been recently published [7], [8], [9]. This review focus on the family of voltage-gated potassium channels ether à go-go (EAG) and its interesting relationship to cancer. Because of their oncogenic properties, distribution, modulation and pharmacology, EAG channels have gained interest as potential diagnostic markers and membrane therapeutic targets for cancer.
Section snippets
Ether à go-go channels
In 1969, several mutants from the fruit fly Drosophila melanogaster were produced following the treatment of adult males by ethyl methane sulfonate [10]. The mutants presented shaking of the legs under ether anesthesia and independent gene loci were found to be involved. One of these mutants exhibited a slow and rhythmic leg-shaking behaviour; the locus involved was then named ether à go-go (eag).
Further evidences including the observation that eag mutants presented a high frequency of
Cell-cycle and EAG
Indicative data that EAG might be related to or modulated during cell-cycle appeared when electrophysiological studies showed that currents with biophysical and pharmacological properties resembling those of erg channels were present in neuroblastoma cell lines; the voltage-dependent properties of such currents varied widely in unsynchronized cells but the variability was greatly reduced when the cells were synchronized in the G1 phase of the cell cycle [23].
Later on, Walter Stühmer's group
Hypothetical scenarios on oncogenicity mechanisms
Potassium channels activity has been related to cell cycle progression, oncogenesis and proliferation, and although the precise mechanism involved has not been elucidated, several hypothesis have been suggested [reviewed in Refs. [7], [8], [9], [56]]. Potassium efflux through potassium channels induces hyperpolarization and changes in cell volume. Hyperpolarization increases the driving force for calcium ions—which might interact with cell cycle proteins—and on the other hand, cell size has
Conclusions
Expression and channel activity studies have highlighted the tight association between EAG and cancer; furthermore, modulation and pharmacological experiments have provided important clues for the potential therapeutic use of EAG in cancer treatment.
Because of its restricted distribution in normal tissues and its more ubiquitous distribution in cancer cells, EAG channels represent promising tools for the development of improved diagnose cancer methods. In addition, since channel inhibition
Acknowledgements
The author is deeply grateful to Walter Stühmer and Luis Pardo (MPI, Göttingen Germany) for supporting significantly his scientific career. The author's laboratory has received financial support by the Consejo Nacional de Ciencia y Tecnología.
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