There is increasing evidence that mitochondria play an important role in the control of cytosolic Ca²⁺ signaling. We have investigated here the effects of inhibiting the main mitochondrial Ca²⁺ exit pathway, the mitochondrial Na⁺/Ca²⁺

exchanger (MNCE), on Ca²⁺ release and cytosolic Ca²⁺ oscillations. In HeLa cells, the specific MNCE inhibitor CGP37157 activated histamine-induced Ca²⁺ release from the endoplasmic reticulum and increased the size of the cytosolic Ca²⁺ peak induced by histamine. CGP37157 also changed the pattern of the Ca²⁺ oscillations induced by histamine from a high-frequency irregular one to a lower frequency baseline spike type. This change in single cell Ca²⁺ dynamics produced however little changes in the average Ca²⁺ values of a large cell population. In human fibroblasts, CGP37157 increased the frequency of the baseline oscillations in cells having spontaneous activity and induced the generation of oscillations in cells without spontaneous activity. This effect was dose-dependent, disappeared when the inhibitor was washed out and was not mimicked by mitochondrial depolarization. CGP37157 increased also mitochondrial [Ca²⁺] and ATP production in histamine-stimulated HeLa cells, although the effect on ATP production was only transient. Our results suggest that the mitochondrial Na⁺/ Ca²⁺ exchanger directly modulates inositol 1,4,5-trisphosphate-induced Ca²⁺ release and in that way controls cytosolic Ca²⁺ oscillations.