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Elevated levels of potassium (K + ) promote maturation and survival of cerebellar granule neurons in culture. When switched from a culture medium containing high K + (25 mM) to one with low K + (5 mM) mature granule neurons undergo death by apoptosis. The mechanism by which high K + promotes neuronal survival and conversely inhibits apoptosis) is unclear. Several pieces of evidence indicate that an increase in intracellular calcium (Ca 2+ ) resulting from depolarization mediated-influx of extracellular Ca 2+ is necessary. We examined the effect of thapsigargin on granule neuron cultures. Thapsigargin is an inhibitor of the endoplasmic reticular Ca 2+ ATPase causing a depletion of Ca 2+ from internal stores. this treatment would therefore be expected to raise intracellular cytosolic Ca 2+ without membrane depolarization. We find that treatment of mature neurons with thapsigargin at doses ⩾5 nM inhibits death resulting from the lowering of extracellular K + . The survival effect of thapsigargin was not affected by inhibitors of extracellular Ca 2+ influx including nifedipine, verapamil, methoxyverapamil, Mg 2+ , and Ni 2+ , nor was it inhibited by the NMDA receptor antagonist, MK801. We have further examined whether thapsigargin could substitute for elevated K + during the maturation of granule cells. Unexpectedly, treatment of younger (immature) neuronal cultures with the same dose of thapsigargin (5 nM) induced cell death. DNA fragmentation analysis suggested that death was due to apoptosis and not toxicity. As observed with the survival effect on mature neurons, the lethal effect of thapsigargin on immature granule cells was not prevented by inhibitors of Ca 2+ influx.