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bioRxiv · 10.1101/597088

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

Yang, M.·James, A. D.·Suman, R.·Kasprowicz, R.·Nelson, M.·O'Toole, P.·Brackenbury, W. J.
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Abstract

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.

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Yang, M., James, A. D., Suman, R., Kasprowicz, R., Nelson, M., O'Toole, P., Brackenbury, W. J.. 2019-04-03. Voltage-dependent activation of Rac1 by Nav1.5 channels promotes cell migration. https://doi.org/10.1101/597088

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