We have previously shown that the presence of extracellular glucose is essential for optimal Ca2 signaling in J774 macrophages. Incubation of these macrophages in buffer containing 2-deoxyglucose (2dGlc) or under glucose-free conditions resulted in a partial release of Ca2 from IPs-sensitive stores and a subsequent inhibition of Ca2 signals. This inhibition did not correlate with the decrease in intracellular ATP levels under these conditions. Glucose deprivation or 2dGlc treatment of these macrophages also caused an inhibition in capacitative entry of Ca2' Our hypothesis is that these effects are mediated via changes in intracellular levels of glucose-6-phosphate (Glc-6-P). In permeabilized J774 cells, we observed that Glc-6-P causes an increase in the thapsigargin-releasable pool of Ca2. In liver microsomes, Glc-6-P has been shown to augment ATP-dependent sequestration of Ca2. In the case of liver this effect is related to the import of Glc-6-P into the endoplasmic reticulum where it is subsequently hydrolyzed by the intralumenal Glc-6-phosphatase. Although the presence of Glc-6-phosphatase has been demonstrated in macrophages, its activity and functional significance remains to be characterized. We are currently investigating the possibility that a pathway, parallel to that in liver, for Glc-6-P import and its hydrolysis by Glc-6-phosphatase exists in macrophages. This may elucidate a mechanism for the effect of Glc-6-P on Ca2 sequestration in J774 cells.