Fig. 4

Roles of cytosolic Cl⁻, ion transporters and ion/water channels in cell migration. When cells migrate, cells need to change cell shape. Na⁺-K⁺-2Cl⁻ cotransporter 1 (NKCC1) and aquaporin (AQP) are expressed on the migrating side membrane. NKCC1 is involved in Cl⁻ uptake into the cytosolic space with Na⁺ and K+ [197, 209,210,211,212]. The uptake of these ions results in an influx of water into the cytosolic space via AQP through an increase in cytosolic osmolarity [196]. The movement of Cl⁻, Na⁺, K⁺ and water causes an increase in cell volume accompanied with [Cl⁻]_c elevation, which promotes tubulin polymerization (elongation) [212] by inhibiting GTPase activity (see Fig. 2B). Similar to tubulin polymerization, actin monomers are enhanced to be polymerized. Then, cells migrate via these processes. On the one hand, K⁺-Cl⁻ cotransporter (KCC), volume-regulated anion channel (VRAC), Ca²⁺-activated K⁺ channel (K⁺_Ca3.1) and AQP are expressed on the tail end membrane of cell migration and excretes Cl⁻ with K⁺ to the extracellular space via KCC, VRAC and K⁺_Ca3.1 [197, 212]. Water efflux to the extracellular space via AQP is caused by a decrease in cytosolic osmolarity due to excretion of these ions. The movement of Cl⁻, K⁺ and water results in a decrease in cell volume accompanied with [Cl⁻]_c diminution, which leads to tubulin depolymerization (shortening) at the tail end of the cell migration [212] by activating GTPase (see Fig. 2C). WNK activated by lowered [Cl⁻]_c induces phosphorylation (activation) of OSR1/SPACK, which increases activity of NKCC1 by phosphorylating NKCC1 [208]. Thus, WNK is importantly involved in cell migration [208]