Inhibition of the M-current in PC12 cells by bradykinin has been studied under whole-cell recording conditions. In cells dialyzed with GTP-gamma-S, bradykinin produced a total and irreversible M-current suppression, while the inhibition was attenuated in cells dialyzed with GDP-beta-S. Inhibition occurred in cells pretreated with pertussis toxin, while this treatment prevented the modulation of Ca2+ currents by muscarine. The rate and extent of inhibition increased with the level of intracellular Ca2+ from 0 to 70 nM. These results indicate that a pertussis toxin insensitive G-protein mediates the action of bradykinin on the M-current, and some steps in the second messenger cascade are modulated by Ca2+.