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.