Voltage-dependent activation of Rac1 by Nav1.5 channels promotes cell migration

Changes in ion channel activity can regulate the plasma membrane potential (Vm) and alter cancer cell migration as a result of altered ion flux. However, the mechanism by which Vm regulates motility remains unclear. Here, using patch clamp recording, we show that the Nav1.5 voltage-gated Na+ channel carries a steady state inward persistent Na+ current which reversibly depolarizes the resting Vm at the timescale of minutes. Immunocytochemistry and confocal microscopy reveal that this Nav1.5-dependent Vm depolarization increases Rac1 colocalization with phosphatidylserine, to which it is anchored at the leading edge of migrating cells, promoting Rac1 activation. Combining a genetically-encoded FRET biosensor of Rac1 activation with morphological analysis shows that depolarization-induced Rac1 activation results in the acquisition of a motile mesenchymal-like cellular phenotype. By identifying Nav1.5-mediated Vm 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 voltage-dependent mechanism for Rac1 activation, which fine tunes cell migration in response to ionic and/or electric field changes in the local microenvironment.