It has been reported that activation of potassium channel is involved in the apoptosis of hippocampal neurons induced by in vivo ischemia and in vitro hypoxia. Recently, cell shrinkage is proposed as an early prerequisite to apoptotic events leading to cell death. To understand the mechanism underlying potassium channel-mediated neuronal apoptosis, the temporal changes in neuronal cell body volume and the involvement of potassium channel in the apoptotic volume decrease were examined in a model of staurosporine (STS)-induced apoptosis of cultured hippocampal neurons. Nonselective potassium channel blocker tetraethylammonium (TEA) or raising extracellular K⁺ concentration significantly prevented STS-induced neuronal cell death. A similar neuroprotection was also observed by treatment with the selective high-conductance calcium-activated potassium channel (BK) blockers iberiotoxin and paxilline. These results indicate that potassium channels, especially BK channels, contribute to STS-induced neuronal apoptosis. Moreover, STS induced an early cell body volume decrease and this cell shrinkage was completely blocked by TEA or high extracellular K⁺. It is suggested that potassium efflux may be involved in the apoptotic volume decrease, which is probably one of the mechanisms underlying mediation of neuronal apoptosis by potassium channel.