The basic structure of different nAChR subunits is quite similar, but the large cytoplasmic loop is highly divergent, which accounts in part for the functional differences and differences in the distribution (39), assembly (40), and other characteristics of nAChR subunits. This cytoplasmic loop is also important for interaction with intercellular proteins, which could increase the stability of α4β2 nAChRs (41), as well as post-translational modification of the α4 subunit (42). Our imaging study showed that for nonsmokers, specific rare variants in the CHRNA5 gene region encoding the cytoplasmic loop could increase the availability of α4β2 nAChRs in multiple brain regions. In addition, a nonsynonymous rare variant seems to have a bigger effect than the synonymous rare variants (Figure 3). One possible explanation for the difference in nAChR availability observed in the subject with the nonsynonymous rare variant is that increased availability of α4β2 nAChRs compensates for damaged protein function. Alternatively, an increase in stability of the mutated α4 protein could increase baseline nAChR function, providing protection against further increases by the nicotine in tobacco. The results from this imaging study
