The interaction between ATP- and high K(+)-evoked increase in intracellular free calcium concentration ([Ca2+]i) was investigated to gain an insight into the mechanism of interaction of ATP with voltage-sensitive calcium channels. [Ca2+]i was measured in the neuronal model, neuroblastoma x glioma hybrid cells (NG 108-15), using the fluorescence indicator fura-2. In the presence of 1.8 mM extracellular Ca2+, ATP induced a rapid, concentration-dependent increase in [Ca2+]i. High K+ (50 mM) evoked a [Ca2+]i rise from 109 +/- 11 nM to 387 +/- 81 nM (n = 16). The application of either of these two [Ca2+]i-increase provoking agents in sequence with the other caused impairment of the latter effect. The mutual desensitization of the responses to ATP and high K+ strongly suggests that both agents rely at least in part on the same source of Ca2+ for elevation of [Ca2+]i in NG 108-15 cells.