Voltage-dependent activation of Rac1 by Na_v1.5 channels promotes cell migration

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.

Sodium homeostasis in the tumour microenvironment

“…Additional approaches, including measurement of 22 Na radioisotope assimilation rate by atomic absorbance spectrophotometry, live cell imaging using the fluorescent Na + reporter SBFI-AM, and 23 Na magnetic resonance imaging ( 23 Na MRI; Box 1) have broadly confirmed these observations in cultured cells and cancer patients (22)(23)(24)(25)(26)(27).…”

Potassium channel-driven bioelectric signaling regulates metastasis in triple-negative breast cancer

“…Previously it has been reported that breast cancer cells are less negative than their normal counterparts and that blocking sodium channels inhibits cell migration and invasion in MDA-MB-231 and MCF7 cells 9,47,48 , however if these effects are RMPdependent is not noted. In contrast, our results suggest that hyperpolarization via K + channel expression leads to increased breast cancer cell invasion.…”

TRP Channels Regulation of Rho GTPases in Brain Context and Diseases

“…Other possible mechanisms for Rac1 regulation by TRPM4 could be the regulation of local changes in membrane potential. For instance, voltage-gated Na + channel Nav1.5 has been proposed to promote Rac1 activity by producing membrane potential depolarization in breast cancer cells ( Yang et al, 2020 ). Nav1.5-induced membrane potential depolarization causes Rac1 activation by promoting local redistribution of phosphatidylserine, an anionic phospholipid to which Rac1 binds, and known to be important for its activation ( Finkielstein et al, 2006 ; Yang et al, 2020 ).…”

“…For instance, voltage-gated Na + channel Nav1.5 has been proposed to promote Rac1 activity by producing membrane potential depolarization in breast cancer cells ( Yang et al, 2020 ). Nav1.5-induced membrane potential depolarization causes Rac1 activation by promoting local redistribution of phosphatidylserine, an anionic phospholipid to which Rac1 binds, and known to be important for its activation ( Finkielstein et al, 2006 ; Yang et al, 2020 ). Interestingly, TRPM4 facilitates cellular depolarization in bone marrow-derived mast cells (BMMC) ( Vennekens et al, 2007 ), HeLa ( Simon et al, 2010 ), and HEK293 cells ( Fliegert et al, 2007 ).…”