Arizona State University,
Keywords: ERK signaling pathway, EGFR, electric field stimulation, microelectrodes
Summary:The dynamics of extracellular-signal-regulated kinase (ERK) signaling regulates a wide variety of stimulated cellular processes and plays an important role in cell survival, motility, differentiation and proliferation. Here we show that specific alternative current electric field (EF) in the tens of KHz could non-invasively activate EGFR-Ras-ERK signaling pathway with precise timing and single-cell resolution, where electroporation or Faradaic processes have been deliberately avoided by using high-k dielectric passivated microelectrodes. We have shown that the ERK activities can be synchronized with the response time independent of the distance from the electrodes, suggesting that the inter-cellular communication and diffusion-limited processes are not involved. Series of blocker tests pinpointed that the ERK activation were triggered by EF induced EGF-independent phosphorylation of EGFR without changes in pH, Ca2+ concentration or reactive oxygen species. Interestingly, we also discovered that the cell response was sensitive to the waveform and timing of the EF, and that inhibition of ERK could also be controlled with different dynamic characteristics, strongly suggesting the electrostatic nature of the coupling between AC EF and the membrane protein. Our work suggests a new exciting possibility that the dynamic signaling initiated by membrane proteins can be non-invasively and locally modulated by specifically tuned EF.