, 2009). At present, the molecular pathway(s) by which sodium channel activity participates in the regulation of intracellular and extracellular pH of cancer cells is not known, but it has been suggested to involve interactions with the sodium-proton exchanger, bicarbonate transporters, vacuolar H+-ATPase, and/or monocarboxylate transporters (Gillet et al., 2009). Sodium channel activity is also likely to affect cancer cells’ membrane potential, which has been linked to their proliferation and migration (Yang and Brackenbury, 2013). In in vitro assays of cancer cell invasiveness, blockade, or knockdown of sodium channels with TTX, phenytoin or small interfering RNA

(siRNA) has been shown to significantly attenuate directional motility and cell migration (Roger et al., 2003, Fraser et al., 2005, Brackenbury et al., 2007, Brackenbury, 2012 and Yang et al., 2012). At the in vivo level, it has been reported in a rat model Volasertib manufacturer of prostate cancer that blocking sodium channel activity with TTX reduces the number of lung metastases by 40% and Caspase pathway significantly prolongs lifespan (Yildirim et al., 2012). Whether

targeted sodium channel blockade or knockdown can contribute to cancer treatment is not yet known, but higher levels in more metastatic cells suggest these channels as potential biomarkers (Diss et al., 2005). Although it is clear that sodium channels participate in or regulate multiple functions within a spectrum of nonexcitable cell types, we presently have only hints about the underlying molecular mechanism(s). Extrapolating from the small number of cell types in which mechanisms linking sodium channels to cell function have been studied, it seems likely, in fact, that sodium channels affect physiological responses of cells by multiple pathways (Figure 4). In a study on astrocytes, Sontheimer et al. (1994) suggested a mechanism medroxyprogesterone in which sodium channels provide a route for a small sustained Na+ influx, which is necessary for continued operation of Na+/K+-ATPase. In these cells, sodium channel

blockade with TTX attenuates Na+/K+-ATPase activity, reduces astrocyte [Na+]I, and with prolonged exposure, leads to cell death. This cascade, in which voltage-gated channels provide a route for Na+ ion influx, which is required for maintaining [Na+]i at concentrations necessary for activity of the sodium pump, suggests that the flux of Na+ ions through sodium channels may provide a feedback loop that, in turn, modulates the ability of astrocytes to regulate K+ levels in the extracellular space. It is not yet known whether sodium channels contribute to the regulation of Na+/K+-ATPase activity in a similar manner in other cell types. Observations on T lymphocytes suggest that sodium channel activity can trigger calcium signals, which, in turn, fine-tune the effector functions of these cells.