Recent evidence suggests a major role for ionic fluxes in apoptotic cell death and apoptotic volume decrease. Cerebellar granule neurons (CGN) undergo apoptosis when they are treated with staurosporine or camptothecin (CPT) or when cells are transferred from high extracellular potassium (25 mM KCl [K+](e), K25) to low potassium concentration (5 mM KCl [K+](e), K5). In this study we described that all three apoptotic conditions induced apoptotic volume decrease in CGN and that two different potassium channel blockers, cesium (Cs+) and tetraethylammonium (TEA(+)), prevented the apoptotic volume decrease, caspase-3 activation, nuclear condensation and cell death induced by K5 and CPT, but not by staurosporine. Cs+ and TEA(+) also blocked membrane currents generated in K5 conditions in CGN. On the other hand, non specific CL channel blockers such as 4,4'-diisothiocyanato-stilbene-2,2'-disulfonic acid (DIDS) prevented loss of cell volume induced by K5 or staurosporine. Only the Cl channels blocker but not the K F channels blockers protected from staurosporine-induced death of CGN. These data suggest that ionic fluxes play a key role in the activation of the apoptotic volume decrease and apoptotic death of CGN, but the fine mechanism seems to depend on the apoptotic condition. (C) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.