However, the hypothesis of a ‘double whammy’ scenario is supported by the fact that the risk of lung cancer that can be attributed to the α3/α5/β4 variant is higher than what one could explain by the variant's effect on smoking quantity.2 This suggests a direct link between α3/α5/β4 and lung cancer mediated by non-neuronal nAChRs, which are engaged peripherally in functions beyond neurotransmission. Consistent with this notion, nicotinic receptor antagonists can block the nitrosa-mine-dependent malignant transformation of respiratory cells in vitro.12 In addition, tobacco smoke and nicotine can both mediate the stepwise overexpression of nAChR subtypes, which leads to increased Ca+ + permeability in exposed cells. Thus, a switch in the nAChR composition (involving α3 and α5 subunits, among others) could change receptor function, leading to profound pathologic effects in cells exposed to nicotine.13 To investigate this hypothesis further, it may now be interesting to revisit the early evidence suggesting a role for nAChRs in the regulation of cell-to-cell communications, adhesion and motility.14
