Whole cell, voltage clamp experiments were performed in vesicles derived from frog skeletal muscle plasma membranes to characterize the influence of ATP on the kinetic properties of fast inactivating K+ currents (I-A). I-A was recorded in ATP-free solutions. Peak I-A decayed with a time constant of 27 ms at large depolarizations. Steady state inactivation reached half maximal values at -66 mV. In the presence of ATP, these values were 196 ms and -41 mV, respectively, indicating a major effect of ATP on inactivation. In contrast, activation of I-A was unaffected by ATP. The protein kinase C (PKC) inhibitors, H7 and staurosporine, greatly prevented the effects of ATP on inactivation. Inactivation remained unchanged by the protein kinase A inhibitor HA1004 or by the catalytic subunit of cAMP protein kinase. We conclude that ATP decreases inactivation of skeletal muscle I-A and that this effect may be mediated by protein kinase C. (C) 2002 Elsevier Science (USA).