KCNJ15/Kir4.2 couples with polyamines to sense weak extracellular electric fields in galvanotaxis

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 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.

Electrophoresis of cell membrane heparan sulfate regulates galvanotaxis in glial cells

“…Results from galvanotaxis experiments in response to changes in media pH and viscosity also provide support for this mechanism (Allen et al, 2013). Membrane components such as ConA receptors, ricin receptors, sialic acids and EGF receptor (EGFR) have been shown to be polarized in an electric field (Poo et al, 1979;Zagyansky and Jard, 1979;Fang et al, 1999;Finkelstein et al, 2007;Nakajima et al, 2015). However, the identity of a macromolecule that exhibits both electrophoretic polarization and is also necessary for galvanotaxis has not been reported.…”

“…Proposed explanations for galvanotaxis include electrophoretic distribution of charged membrane components (Jaffe, 1977;Poo and Robinson, 1977;Allen et al, 2013), asymmetric activations of ion channels (Yang et al, 2013;Nakajima et al, 2015), and membrane-associated electro-osmotic forces (McLaughlin and Poo, 1981). Interestingly, while most cell types exhibit galvanotaxis, the response can be either cathodic or anodic, suggesting that there may be competing mechanisms (Mycielska and Djamgoz, 2004;Sato et al, 2009;Sun et al, 2013).…”

Targeting polyamine metabolism for cancer therapy and prevention

“…An intriguing new function for the natural polyamines has been proposed related to its role in regulating the inward rectifying channel for potassium. Nakajima et al [10] have provided data, indicating that the polyamines play an essential role in sensing weak electric fields that guide cell migration known as galvanotaxis. These novel findings implicate yet another role for polyamines in cell migration/metastasis that clearly has significance in cancer.…”

Voltage-gated ion channels mediate the electrotaxis of glioblastoma cells in a hybrid PMMA/PDMS microdevice

“…VGKCs are involved in diverse physiological and pathological processess regulating the repolarization of neuromuscular action potential, calcium homeostasis, cellular proliferation, migration, and cancer proliferation [83][84][85][86][87][88][89] . Voltage-gated potassium channel K v 1.2 90 and non voltage-gated inwardly-rectifying potassium channel K ir 4.2 91 have been shown to be involved in the sensing of electric field and signaling of cell electrotaxis. The potassium ion transporters confer biophysical signals that are key for regulating stem cells and tumor cells behavior in microenvironment 92 .…”