Incubation of PC12 cells with S-100 protein induces a rapid (0.5–1.0 min) rise of intracellular Ca²⁺ which lasts for the whole period of incubation. This effect is abolished in a Ca²⁺-free medium or in the presence of 1.0 μ M Ni²⁺, an inhibitor of calcium channels. The rise in intracellular Ca²⁺ is followed by a progressive increase of cells undergoing degeneration and death. This event is accompanied by the appearance of apoptotic bodies and DNA fragmentation typical of the process known as apoptosis. S-100-induced cell death is prevented by 1 μM Ni²⁺ or by 0.1 nM cycloheximide, suggesting the involvement of new protein synthesis.

It is postulated that the binding of S-100ab to specific sites present in PC12 cells is followed by the formation of Ca²⁺ channels and/or the stimulation of pre-existing ones with consequent increase of Ca²⁺ influx and activation of a process of cell death.