Nicotinic receptor-induced apoptotic cell death of hippocampal progenitor cells.
Nicotine has many effects on CNS functions, presumably through its action on neuronal nicotinic acetylcholine receptors (AChRs). One subclass 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-Bgt-AChR activation by low doses of nicotine results in apoptotic cell death of both primary and immortalized hippocampal progenitor cells. In HC2S2-immortalized hippocampal progenitors, nicotine is cytotoxic to undifferentiated cells, whereas it spares the same cells once differentiation has been induced. The activation of alpha-Bgt-AChRs by nicotine results in the induction of the tumor suppressor protein p53 and the cdk inhibitor p21. The cytotoxic effect of nicotine is dependent on extracellular calcium levels and is probably attributable to the poor ability of undifferentiated progenitors to buffer calcium loads. The major calcium buffer in these cells, calbindin D28K, is present only after differentiation has been induced. Furthermore transfection of undifferentiated cells with calbindin results in dramatic protection against the cytotoxic effects of nicotine. These results show that nicotine abuse could have significant effects on the survival of progenitor populations in the developing and adult brain and also suggest an endogenous role for alpha-Bgt-AChRs in neuronal development and differentiation.
Laboratory of Genetics, The Salk Institute, La Jolla, California 92037, USA.
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Berger
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Gage
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Vijayaraghavan
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002038:Bungarotoxins / Q000494:pharmacology; D064092:Calbindin 1; D064026:Calbindins; D002118:Calcium / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000502:physiology; D053938:DNA Fragmentation; D006624:Hippocampus / Q000166:cytology*; D009419:Nerve Tissue Proteins / Q000494:pharmacology; D009538:Nicotine / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D011978:Receptors, Nicotinic / Q000502:physiology*; D064030:S100 Calcium Binding Protein G / Q000494:pharmacology; D013234:Stem Cells / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D002038:Bungarotoxins; C576500:Calb1 protein, rat; D064092:Calbindin 1; D064026:Calbindins; D009419:Nerve Tissue Proteins; D011978:Receptors, Nicotinic; D064030:S100 Calcium Binding Protein G; D016159:Tumor Suppressor Protein p53; D009538:Nicotine; D002118:Calcium