A schematic of NaKA and NHE3 activity on the leading edge of cathode (Calvaria)- or anode (SaOS-2)-directed cells during electrotaxis. Cells are polarized with a well-defined front and back during electrotaxis. Independent from the migration direction, NaKA is relocated from the cytoplasm to the protrusions, wherein its enhanced activity on the leading edges of cells and results in a hyperpolarized cell membrane, whereas the rear end membrane remains depolarized. Active NHE3 and consistently elevated pHi levels appear to be preferentially localized to the protrusions at the leading edges of cathode-directed cells, but not in anode-directed cells, which indicates a cathode-specific directional sensing. At the mechanical level, the colocalization of NaKA with vinculin at focal adhesion sites and the colocalization of active NHE3 with the filopodia marker ß-actin suggest a direct action for NaKA and for NHE3 in adhesion turnover and in filopodia formation, respectively.