Parallel signaling pathways regulate excitable dynamics differently for pseudopod formation in eukaryotic chemotaxis

In eukaryotic chemotaxis, parallel signaling pathways regulate the spatiotemporal pseudopod dynamics at the leading edge of a motile cell through characteristic dynamics of an excitable system; however, differences in the excitability and the physiological roles of individual pathways remain to be elucidated. Here we found that two different pathways, soluble guanylyl cyclase (sGC) and phosphatidylinositol 3-kinase (PI3K), exhibited similar all-or-none responses but different refractory periods by simultaneous observations of their excitable properties. Due to the shorter refractory period, sGC signaling responded more frequently to chemoattractants, leading to pseudopod formation with higher frequency. sGC excitability was regulated negatively by its product, cGMP, and cGMP-binding protein C (GbpC) through the suppression of F-actin polymerization, providing the underlying delayed negative feedback mechanism for the cyclical pseudopod formation. These results suggest that parallel pathways respond on different time-scales to environmental cues for chemotactic motility based on their intrinsic excitability. Key words: cGMP signaling, chemotaxis, excitability, pseudopod formation