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

Ming Yang, Andrew David James, Rakesh Suman, Richard Mark Robert Kasprowicz, Michaela Nelson, Peter John O'Toole, William John Brackenbury

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Ion channels can regulate the plasma membrane potential (Vm) and cell migration as a result of altered ion flux. However, the mechanism by which Vm regulates motility remains unclear. Here, we show that the Nav1.5 sodium channel carries persistent inward Na+ current which depolarizes the resting Vm at the timescale of minutes. 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. A genetically-encoded FRET biosensor of Rac1 activation shows that depolarization-induced Rac1 activation
results in acquisition of a motile 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 mechanism for Rac1 activation, which fine tunes cell migration in response to ionic and/or electric field changes in the local microenvironment.
Original languageEnglish
Number of pages23
JournalJournal of cellular physiology
Early online date15 Oct 2019
Publication statusE-pub ahead of print - 15 Oct 2019

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© 2019 The Authors

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