Previous data have shown that protein kinase C (PKC) participates in the mechanism of sperm-induced calcium oscillations in mammalian oocytes, but the actual role of this enzyme in the oscillation mechanism is still unknown. In this study we show that drugs modulating PKC activity disturb the oscillations induced by spermatozoa, thimerosal and ryanodine, but in a different way for each of the three oscillogenic agents. Moreover, PKC inhibition interferes with the return of the intracellular free calcium concentration to basal values during the sperm- and ryanodine-induced calcium oscillations, but not during the thimerosal-induced calcium oscillations. When the PKC-modulating drugs were applied before any of the three oscillogens, the subsequent calcium oscillations were also disturbed. However, the first calcium spike induced by spermatozoa and thimerosal was little influenced by PKC activation or inhibition. On the other hand, ryanodine failed to produce any calcium response when the PKC activity was clamped to a high level. These data suggest that sustained high PKC activities impede calcium oscillations by interfering with the opening of the ryanodine-sensitive calcium release channel, whereas sustained low activities of the enzyme paralyse the channel in the open state.