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

TY - JOUR

T1 - Voltage-dependent activation of Rac1 by Nav1.5 channels promotes cell migration

AU - Yang, Ming

AU - James, Andrew David

AU - Suman, Rakesh

AU - Kasprowicz, Richard Mark Robert

AU - Nelson, Michaela

AU - O'Toole, Peter John

AU - Brackenbury, William John

N1 - © 2019 The Authors

PY - 2019/10/15

Y1 - 2019/10/15

N2 - 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 activationresults in acquisition of a motile phenotype. By identifying Nav1.5-mediated Vmdepolarization 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.

AB - 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 activationresults in acquisition of a motile phenotype. By identifying Nav1.5-mediated Vmdepolarization 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.

U2 - 10.1002/jcp.29290

DO - 10.1002/jcp.29290

M3 - Article

SN - 0021-9541

JO - Journal of cellular physiology

JF - Journal of cellular physiology

ER -