Voltage-dependent activation of Rac1 by Nav1.5 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.