The epithelial sodium channel mediates the directionality of galvanotaxis in human keratinocytes

Abstract

Cellular directional migration of in an electric field (galvanotaxis) is one of the mechanisms guiding cell movement in embryogenesis and in skin epidermal repair. The epithelial sodium channel (ENaC) in addition to its function of regulating sodium transport in kidney has recently been found modulate cell locomotory speed. Here we tested if ENaC has an additional function of mediating the directional migration of galvanotaxis in keratinocytes. Genetic depletion of ENaC completely blocks only galvanotaxis and does not decrease migration speed. Overexpression of ENaC is sufficient to drive galvanotaxis in otherwise unresponsive cells. Pharmacologic blockade or maintenance of the open state of ENaC also decreases or increases, respectively, galvanotaxis, suggesting that channel open state is responsible for the response. Stable lamellipodial extensions formed at the cathodal sides of wild type cells at the start of galvanotaxis; these were absent in the ENaC knockout keratinocytes, suggesting that ENaC may mediate galvanotaxis by generating stable lamellipodia that steer cell migration. We provide evidence that ENaC is required for directional migration of keratinocytes in an electric field, supporting a role for ENaC in skin wound healing.