Adenosine triphosphate (ATP)-sensitive potassium (K-ATP) channels couple cell metabolism to electrical activity. Phosphatidylinositol phosphates (PIPs) profoundly antagonized ATP inhibition of K-ATP channels when applied to inside-out membrane patches. It is proposed that membrane-incorporated pips can bind to positive charges in the cytoplasmic region of the channel＇s K(ir)6.2 subunit, stabilizing the open state of the channel and antagonizing the inhibitory effect of ATP. The tremendous effect of pips on ATP sensitivity suggests that in vivo alterations of membrane PIP levels will have substantial effects on K-ATP channel activity and hence on the gain of metabolism-excitation coupling.