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duction of amyloid beta (Abeta) upon extracellular Ca(2)(+)removal and its subsequent addback. The aim of this study was to investigate the effect of the overexpression of CALHM1 and P86L-CALHM, upon Abeta treatment, on the following: (i) the intracellular Ca(2)(+)signal pathway; (ii) cell survival proteins ERK1/2 and Ca(2)(+)/cAMP response element binding (CREB); and (iii) cell vulnerability after treatment with Abeta. Using aequorins to measure the effect of nuclear Ca(2)(+)concentrations ([Ca(2)(+)]n ) and cytosolic Ca(2)(+)concentrations ([Ca(2)(+)]c ) on Ca(2)(+)entry conditions, we observed that baseline [Ca(2)(+)]n was higher in CALHM1 and P86L-CALHM1 cells than in control cells. Moreover, exposure to Abeta affected [Ca(2)(+)]c levels in HeLa cells overexpressing CALHM1 and P86L-CALHM1 compared with control cells. Treatment with Abeta elicited a significant decrease in the cell survival proteins p-ERK and p-CREB, an increase in the activity of caspases 3 and 7, and more frequent cell death by inducing early apoptosis in P86L-CALHM1-overexpressing cells than in CALHM1 or control cells. These results suggest that in the presence of Abeta, P86L-CALHM1 shifts the balance between neurodegeneration and neuronal survival toward the stimulation of pro-cytotoxic pathways, thus potentially contributing to its deleterious effects in AD.