Figure 2.

Cellular Na⁺ import and export mechanisms. Cells exhibit a diverse repertoire of Na⁺ channels and transporters, many of which exhibit altered expression in cancer (Table 1) and are being explored as potential therapeutic targets (Table 2). The activity and conductance of these channels is regulated by [Na⁺]_i, [Na⁺]_e, membrane potential and auxiliary regulatory proteins. Channels that facilitate Na⁺ influx include voltage gated Na⁺ channels (VGSC), epithelial Na⁺ channels (ENaC), acid-sensing channels (ASIC), glutamate-activated N-methyl-D-aspartate receptors (NMDA), ATP-activated P2X purinoceptor 7 (P2X7) and the G protein-coupled Na⁺ leak channel, non-selective (NALCN). The inward Na⁺ gradient and a hyperpolarised membrane potential are maintained by the ATP-driven Na⁺/K⁺ ATPase. Na⁺ influx is also linked to the transport of numerous other ions and substrates, namely H⁺ efflux (Na⁺/H⁺ exchanger 1, NHE1), Cl^- and K⁺ influx (Na⁺-K⁺-Cl^- cotransporter, NKCC), cytosolic and mitochondrial Ca²⁺ efflux (Na⁺/Ca²⁺ exchanger, NCX and mitochondrial Na⁺-Ca²⁺(Li⁺) exchanger, NCLX, respectively) glucose uptake (sodium-glucose linked transporter, SGLT) and amino acid (AA) uptake. Na⁺/H⁺ exchangers (NHE) are also present on both mitochondria and lysosomes, the latter of which achieve Na⁺ efflux into the cytosol via two-pore channels (TPC) and transient receptor potential mucolipin (TRPML) channels.