Rapid Chemically Induced Changes of PtdIns(4,5)P₂ Gate KCNQ Ion Channels

To resolve the controversy about messengers regulating KCNQ ion channels during phospholipase C-mediated suppression of current, we designed translocatable enzymes that quickly alter the phosphoinositide composition of the plasma membrane after application of a chemical cue. The KCNQ current falls rapidly to zero when phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P₂ or PI(4,5)P₂] is depleted without changing Ca²⁺, diacylglycerol, or inositol 1,4,5-trisphosphate. Current rises by 30% when PI(4,5)P₂ is overproduced and does not change when phosphatidylinositol 3,4,5-trisphosphate is raised. Hence, the depletion of PI(4,5)P₂ suffices to suppress current fully, and other second messengers are not needed. Our approach is ideally suited to study biological signaling networks involving membrane phosphoinositides.