NICOTINIC RECEPTOR-INDUCED APOPTOTIC CELL-DEATH OF HIPPOCAMPAL PROGENITOR CELLS

Nicotine has many effects on CNS functions, presumably through its act ion on neuronal nicotinic acetylcholine receptors (AChRs). One subclas s of AChRs that binds the snake venom toxin alpha-bungarotoxin (alpha- Bgt-AChRs) has been shown to modulate neurotransmission in the brain. We now show that alpha-BgtAChR activation by low doses of nicotine res ults in apoptotic cell death of both primary and immortalized hippocam pal progenitor cells. In HC2S2-immortalized hippocampal progenitors, n icotine is cytotoxic to undifferentiated cells, whereas it spares the same cells once differentiation has been induced. The activation of al pha-Bgt-AChRs by nicotine results in the induction of the tumor suppre ssor protein p53 and the cdk inhibitor p21. The cytotoxic effect of ni cotine is dependent on extracellular calcium levels and is probably at tributable to the poor ability of undifferentiated progenitors to buff er calcium loads. The major calcium buffer in these cells, calbindin D 28K, is present only after differentiation has been induced. Furthermo re transfection of undifferentiated cells with calbindin results in dr amatic protection against the cytotoxic effects of nicotine. These res ults show that nicotine abuse could have significant effects on the su rvival of progenitor populations in the developing and adult brain and also suggest an endogenous role for alpha-Bgt-AChRs in neuronal devel opment and differentiation.