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Journal of Physiology (2001), 532.3, p. 581
© Copyright 2001 The Physiological Society
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Electrophysiologists have been puzzled for more than 10 years by the finding that inhibition of several ion channels by structurally different channel blockers decreases or stops cell growth (for reviews see Nilius & Droogmans, 1994; Wonderlin & Strobl, 1996).
So far, most of the studies have been done on cation channels, but there is now growing evidence that Cl- channels are also critically involved in regulation of the cell cycle. In this issue of The Journal of Physiology, Wondergem and colleagues show that blocking the swelling-activated Cl- current in a non-transformed mouse liver cell line down-regulates hepatocyte proliferation (Wondergem et al. 2001). In addition to providing further evidence for an already well-described phenomenon, the authors add several important new facts. First, they add a new and important cell type to the list of cells in which this phenomenon has been observed; second, they show that the volume or cell swelling-activated Cl- current, ICl,swell, is absent in non-dividing cells; and third, all measures used to inhibit cell proliferation through block of ICl,swell have no detectable effect on the metabolism of the hepatocytes.
The current characterised by Wondergem et al. (2001) exhibits properties similar to those found in most, if not all, proliferating cell types, namely, activation by cell swelling, Eisenman type I halide permeability (SCN- > I- > Br- > Cl- > gluconate), permeability for organic osmolytes and amino acids, outward rectification, block by NPPB, tamoxifen and mibefradil, and dependence on intracellular ATP (Nilius et al. 1997). The channel through which this current permeates has been given different names depending on which of its features has been favoured by the respective investigators (e.g. volume-regulated anion channels (VRAC), volume-activated outwardly rectifying Cl- channels (VSOAC, VSOR, VRClC), etc.). This confusion reflects the absence of any reliable channel candidate identified at the molecular level. However, the 'hepatic' channel is probably part of a ubiquitous family of volume-regulated anion channels (here referred to as VRAC) with at least functionally very similar features. Thus the findings in this paper are likely to be of general importance.
What is known so far about this interesting, although still mysterious, phenomenon? Many cell types swell early during proliferation, possibly due to water influx that accompanies obligatory uptake of amino acids. Swelling usually co-activates K+ and Cl- effluxes which initiate regulatory volume decrease (RVD). Block of such K+ or Cl- channels by compounds having completely different physicochemical properties inhibits cell proliferation (shown in rat microglia, macro- and microvascular endothelium, fibroblasts, neuroblastoma cells, glioma cells, melanoma cells, breast cancer cells, lymphocytes, several types of neurons, and many more) and decreases [3H]-thymidine incorporation. Channel blockers also disrupt events downstream of cell proliferation such as differentiation (e.g. in several myoblastic cells and in PC12 cells), cell migration (e.g. in glioma cells) and angiogenesis, as shown in various models such as the fibrin-, aorta-ring and chick-chorioallantoic membrane assays (for a review see Nilius et al. 1997).
The question remains whether this phenomenon is of any physiological significance or is just an epiphenomenon? Metabolism, mitosis, cell growth and migration are elevated during proliferation compared with cells arrested in the G0/G1 stage in the cell cycle and these are expected to perturb cell volume, which is of fundamental importance for all mammalian cells. It seems therefore beneficial that mechanisms involved in regulating cell volume are activated during cell proliferation. The close linkage between cell proliferation, growth and volume regulation suggests that VRAC may play a role in the cell cycle clock. RVD may ensure that concentrations of critical factors are maintained, including cyclins (D1, 2 and 3 in early G1; E1 and 2 in late G1), cyclin-dependent kinases (CDK 4 and 6 in early G1; CDK 2 in late G1), the cyclin D-CDK substrate of the retinoblastoma gene product pRb, endogenous CDK inhibitors (CDK inhibitors p15, 1, 18, 19, 20, 21, 27 and 57) and cyclin transcription factors (e.g. E2F), all of which are necessary for a controlled progression through the START checkpoint in late G1 (Shankland & Wolf, 2000). This would also explain why the cell cycle is sensitive to blockers of both K+ and Cl- channels since both are required for RVD. During G1/S progression, entry into S is accompanied by intake of amino acids and other metabolic substrates. VRAC could provide an additional pathway for such compounds. Thus, from the viewpoint of cell metabolism, up-regulation of VRAC is likely to be beneficial in helping cells progress through the G1/S transition.
While evidence accumulates that ion channels are important regulators of the cell cycle, the underlying mechanisms remain an enigma and many questions are still open. Very few attempts have been made to differentiate between cell-cycle arrest by ion channel blockers and inhibition of cell proliferation through slowing down of the cell cycle. Recent evidence favours cell arrest, since blocking VRAC arrests human cervical cancer cells in G0/G1 and vice versa, i.e. arresting cell growth in G0/G1 with aphodicolin dramatically reduces VRAC (Shen et al. 2000). The present study further supports the view that the influence of K+ and Cl- channels on cell cycling may be related to volume homeostasis. However, it has also been shown that ion channels influence intracellular Ca2+ concentration, the membrane potential and regulation of the intracellular pH, which all modulate G1/S transition.
The present work is exciting in that it provides new evidence for the importance of Cl- channels in regulating the cell cycle. Future studies must solve the enigma of how this interplay of channels with the cell cycle machinery is organised.
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REFERENCES |
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| NILIUS B. & DROOGMANS, G. (1994). News in Physiological Sciences 9, 105-110 | |
| NILIUS B., EGGERMONT, J., VOETS, T., BUYSE, G., MANOLOPOULOS, V. G. & DROOGMANS, G. (1997). Progress in Bipohysics and Molecular Biology 68, 69-119 | |
| SHANKLAND S. J. & WOLF, G. (2000). American Journal of Physiology - Renal Physiology 278, F515-529 | [Medline] |
| SHEN M.-R., DROOGMANS, G., EGGERMONT, J., VOETS, T., ELLORY, J. C. & NILIUS, B. (2000). Journal of Physiology 529, 385-394 | [Abstract/Full Text] |
| WONDERGEM R., GONG, W., MONEN, S. H., DOOLEY, S. N., GONCE, J. L., CONNER, T. D., HOUSER, M., ECAY, T. W. & FERSLEW, K. E. (2001). Journal of Physiology 532, 661-672 | [Abstract/Full Text] |
| WONDERLIN W. F. & STROBL, J. S. (1996). Journal of Membrane Biology 154, 91-107 | [Medline] |
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