Central role of alpha 7 nicotinic receptor in differentiation of the stratified squamous epithelium

Several ganglionic nicotinic acetylcholine receptor (nAChR) types are abundantly expressed in nonneuronal locations, but their functions remain unknown. We found that keratinocyte alpha 7 nAChR controls homeostasis and terminal differentiation of epidermal keratinocytes required for formation of the skin barrier. The effects of functional inactivation of alpha 7 nAChR on keratinocyte cell cycle progression, differentiation, and apoptosis were studied in cell monolayers treated with alpha -bungarotoxin or antisense oligonucleotides and in the skin of Acra7 homozygous mice lacking alpha 7 nAChR channels. Elimination of the alpha 7 signaling pathway blocked nicotine-induced influx of super(45)Ca super(2+) and also inhibited terminal differentiation of these cells at the transcriptional and/or translational level. On the other hand, inhibition of the alpha 7 nAChR pathway favored cell cycle progression. In the epidermis of alpha 7 super(-/-) mice, the abnormalities in keratinocyte gene expression were associated with phenotypic changes characteristic of delayed epidermal turnover. The lack of alpha 7 was associated with up-regulated expression of the alpha 3 containing nAChR channels that lack alpha 5 subunit, and both homomeric alpha 9- and heteromeric alpha 9 alpha 10-made nAChRs. Thus, this study demonstrates that ACh signaling through alpha 7 nAChR channels controls late stages of keratinocyte development in the epidermis by regulating expression of the cell cycle progression, apoptosis, and terminal differentiation genes and that these effects are mediated, at least in part, by alterations in transmembrane Ca super(2+) influx.