Voltage‐dependent activation of Rac1 by Na v 1.5 channels promotes cell migration

Ion channels can regulate the plasma membrane potential (V m ) and cell migration as a result of altered ion flux. However, the mechanism by which V m regulates motility remains unclear. Here, we show that the Na v 1.5 sodium channel carries persistent inward Na + current which depolarizes the resting V m at the timescale of minutes. This Na v 1.5‐dependent V m depolarization increases Rac1 colocalization with phosphatidylserine, to which it is anchored at the leading edge of migrating cells, promoting Rac1 activation. A genetically encoded FRET biosensor of Rac1 activation shows that depolarization‐induced Rac1 activation results in acquisition of a motile phenotype. By identifying Na v 1.5‐mediated V m depolarization as a regulator of Rac1 activation, we link ionic and electrical signaling at the plasma membrane to small GTPase‐dependent cytoskeletal reorganization and cellular migration. We uncover a novel and unexpected mechanism for Rac1 activation, which fine tunes cell migration in response to ionic and/or electric field changes in the local microenvironment.