Adenosine triphosphate (ATP)-sensitive potassium (K-ATP) channels couple electrical activity to Cellular metabolism through their inhibition by intracellular ATP. ATP inhibition of K-ATP channels varies among tissues and is affected by the metabolic and regulatory state of individual cells, suggesting involvement of endogenous factors. It is reported here that phosphatidylinositol-4,5-bisphosphate (PIP2) and phosphatidylinositol-4-phosphate (PIP) controlled ATP inhibition of cloned K-ATP channels (K(ir)6.2 and SUR1). These phospholipids acted on the K(ir)6.2 subunit and shifted ATP sensitivity by several orders of magnitude. Receptor-mediated activation of phospholipase C resulted in inhibition of K-ATP-mediated currents. These results represent a mechanism for control of excitability through phospholipids.