and PIP as Determinants for ATP Inhibition of [K.sub.ATP] Channels

Adenosine triphosphate (ATP)-sensitive potassium ([K.sub.ATP]) channels couple electrical activity to cellular metabolism through their inhibition by intracellular ATP. ATP inhibition of [K.sub.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 ([PIP.sub.2]) and phosphatidylinositol-4-phosphate (PIP) controlled ATP inhibition of cloned [K.sub.ATP] channels ([K.sub.ir] 6.2 and SUR1). These phospholipids acted on the [K.sub.ir] 6.2 subunit and shifted ATP sensitivity by several orders of magnitude. Receptor-mediated activation of phospholipase C resulted in inhibition of [K.sub.ATP]-mediated currents. These results represent a mechanism for control of excitability through phospholipids.
Modulation of [K.sub.ATP] channels by activation of metabotropic receptors and cell metabolism is an important pathway for regulation of cell excitability (l). A common feature of these regulatory effects is [...]