Extending these observations to human tissue, Black et al. (2013) recently demonstrated the expression of Nav1.5 in late, but not early, endosomes in phagocytosing macrophages within acute MS lesions. Still another example of a role for sodium channels in the regulation of effector functions of nonexcitable cells is provided by dendritic cells (DCs), the antigen-presenting immune cells that function as intermediaries between innate and adaptive immunity. Immature monocyte-derived DCs express Nav1.7 channels, but the expression of these channels is attenuated during maturation (Zsiros et al., 2009). Even if it did not result
in a large increase in intracellular [Na+], the addition of even a small standing sodium conductance (due, check details for SB431542 purchase example, to persistent activation of a small fraction of available channels) would be expected to have a depolarizing effect on resting potential of these cells. A link between Nav1.7 expression and cell function in DCs is suggested by the observation that Nav1.7
current density is significantly greater in CD1a+ immature DCs than in CD1a− immature DCs (Kis-Toth et al., 2011). The presence of a Nav1.7 current is associated with a depolarized resting membrane potential, as predicted by the Goldman-Hodgkin-Katz equation, in CD1a+ DCs, and blockade or knockdown of Nav1.7 in these cells yields a hyperpolarization of the resting membrane potential, which is associated with attenuated mobility and gene expression of matrix metalloproteinase 12 (Kis-Toth et al., 2011). Nav1.7 blockade with TTX also attenuates inflammatory-cytokine-stimulated activation of CD1a+ Idoxuridine DCs and the release of TNF-α and IL-10 from these cells. There is also increasing evidence suggesting that levels of sodium channel expression are correlated with invasiveness and metastatic potential in several types of cancer cells. For example, strongly metastatic breast cancer cells express voltage-sensitive sodium currents, whereas weakly metastatic and normal breast epithelial cells
do not (Fraser et al., 2005 and Yang et al., 2012). Upregulated expression of a neonatal splice form of Nav1.5 has been linked to strong metastatic potential in vitro and breast cancer progression, and there appears to be a correlation between Nav1.5 expression and clinically assessed lymph node invasion (Fraser et al., 2005). Levels of sodium channel expression are also greater in prostate biopsies from patients with cancer than in non-cancer biopsies (Diss et al., 2005). Sodium channel activity has been reported to potentiate the effect of epidermal growth factor (EGF), which enhances the migration and invasiveness of prostate cancer cells (Uysal-Onganer and Djamgoz, 2007), suggesting a potential mechanism linking sodium channel activity to metastatic activity in these cells.