Abstract
Weak electric fields guide cell migration, known as galvanotaxis/electrotaxis. The sensor(s) cells use to detect the fields remain elusive. Here we perform a large-scale screen using an RNAi library targeting ion transporters in human cells. We identify 18 genes that show either defective or increased galvanotaxis after knockdown. Knockdown of the KCNJ15 gene (encoding inwardly rectifying K+ channel Kir4.2) specifically abolishes galvanotaxis, without affecting basal motility and directional migration in a monolayer scratch assay. Depletion of cytoplasmic polyamines, highly positively charged small molecules that regulate Kir4.2 function, completely inhibits galvanotaxis, whereas increase of intracellular polyamines enhances galvanotaxis in a Kir4.2-dependent manner. Expression of a polyamine-binding defective mutant of KCNJ15 significantly decreases galvanotaxis. Knockdown or inhibition of KCNJ15 prevents phosphatidylinositol 3,4,5-triphosphate (PIP3) from distributing to the leading edge. Taken together these data suggest a previously unknown two-molecule sensing mechanism in which KCNJ15/Kir4.2 couples with polyamines in sensing weak electric fields.
Highlights
Weak electric fields guide cell migration, known as galvanotaxis/electrotaxis
Small physiological direct current electrical fields (EFs) are found in living organisms from plants to animals, for example at wounds, regeneration sites and tumours, and provide a strong guidance cue for directional cell migration, a phenomenon termed galvanotaxis/electrotaxis that was first demonstrated over 100 years ago[1,2,3,4]
Ion channels are localized at the plasma membrane and are among the first groups of molecules exposed to extracellular EFs; this category of proteins would be a promising candidate to be the sensor of weak extracellular EFs
Summary
Weak electric fields guide cell migration, known as galvanotaxis/electrotaxis. The sensor(s) cells use to detect the fields remain elusive. Knockdown or inhibition of KCNJ15 prevents phosphatidylinositol 3,4,5-triphosphate (PIP3) from distributing to the leading edge Taken together these data suggest a previously unknown two-molecule sensing mechanism in which KCNJ15/Kir4.2 couples with polyamines in sensing weak electric fields. Galvanotaxis may play a crucial role in wound healing/regeneration and development[7,8,9,10,11,12,13] Interest in using this powerful mechanism to engineer cells and tissues is growing stronger[14]. Ion channels are localized at the plasma membrane and are among the first groups of molecules exposed to extracellular EFs; this category of proteins would be a promising candidate to be the sensor of weak extracellular EFs. We developed a large-scale systematic screen to determine roles for ion channels in sensing weak EFs in galvanotaxis of human cells. We used polydimethylsiloxane materials that adhere to the culture dish base with a water-tight seal that prevents well to well exchange of medium or cells
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