MODULATION OF CA2-GUANINE NUCLEOTIDE LEVELS( INFLUX DEPENDENT ON STORE DEPLETION BY INTRACELLULAR ADENINE)

The effects of a number of metabolic inhibitors on the influx of Ca2activated by stimulation of receptors coupled to inositol 1,4,5-trisph osphate generation or by depletion of intracellular Ca2+ stores with t hapsigarsn were investigated in four different cell types: Ehrlich asc ites tumor cells, Jurkat and HeLa cell lines, and rat hepatocytes. Ind ependently of their chemical structure and site of inhibition, all of these metabolic poisons markedly inhibited Ca2+ influx without signifi cantly affecting Ca2+ release. This inhibition was not due to membrane potential depolarization or to alteration in cytosolic pH but appeare d correlated to a drop in the cellular concentration of ATP. The decre ases in cellular [ATP] were paralleled by decreases in [GTP] and by in creases in [ADP] and [GDP]. The reduction in ATP level necessary to dr astically reduce Ca2+ influx was quite small, e.g. a 50% inhibition fo r a 5% reduction in [ATP], thus within the range of fluctuation presum ably occurring under physiological conditions. We suggest that changes in the adenine or guanine nucleotide concentrations may represent an important modulatory mechanism of Ca2+ influx activated by store deple tion.