Effects of high K+ stimulation on inositol polyphosphate accumulations and intracellular free calcium concentration ([Ca2+]i) were investigated in cultured rat cerebellar granule cells. When the [3H]inositol-labelled cells were stimulated with KCl, concentration-dependent accumulations of [3H]Ins(1,4,5)P3, [3H]InsP5 and [3H]InsP6 were observed. Nifedipine (3 microM), a calcium channel antagonist, inhibited the high (KCl, 90 mM) K(+)-induced accumulations of these inositol polyphosphates. In Ca(2+)-depleted and EGTA-containing (0.1 mM) medium, the high K(+)-induced inositol polyphosphate accumulation were completely inhibited. Similar results were also observed in the case of [Ca2+]i. These results suggest that the rise in [Ca2+]i caused by activation of voltage-dependent calcium channels plays an important roles in the high K(+)-induced accumulation of [3H]Ins(1,4,5)P3, [3H]InsP5 and [3H]InsP6 in cultured rat cerebellar granule cells.