The establishment of CHRNA5–CHNRA3–CHRNB4 as a risk locus for nicotine dependence has opened a window for functional studies seeking to understand etiologic mechanisms. In HEK-293T human embryonic kidney cells, recombinant receptors for the risk allelic variant of rs16969968 are less responsive to the nicotinic receptor agonist epibatidine, whereas the binding capacity and the amount of protein remain the same as those of the wild-type allele59. Consistent with this result, a study in Xenopus laevis oocytes suggested that the receptor with the asparagine risk allele has lower Ca2+ permeability and desensitizes more quickly than the wild-type aspartate allele in the (α4β2)2α5 receptor, a principal subtype of nicotinic receptor in the central nervous system, but not in (α3β4)2α5 or (α3β2)2α5 subtypes, which are mainly located in the peripheral nervous system60. These results collectively suggest that the α5 subunit modulates the activities of nicotinic receptors and that the asparagine allele makes these receptors less efficient, thereby resulting in an increased consumption of tobacco. Of interest, a human imaging study suggested a possible neural mechanism for the effect of the rs16969968 variant61. It was
