In a follow-up to the aforementioned study,33 three variants of human CHRNA4 (encoding for the substitutions R336C, P451L and R487Q) were subjected to detailed functional studies in Xenopus laevis oocytes.18 Electrophysiological studies found changes in the activation by nAChR agonists in channels containing these α4 rare variants, including changes following incubation with nicotine. The authors concluded that sequence variation at CHRNA4 alters the assembly and expression of human α4β2 nAChRs, resulting in receptors that are influenced to a greater extent by nicotine exposure than channels containing the common α4 variant. Specifically, incubation of oocytes transfected with the α4R336C variant with nicotine for 24 h had the same effect on nicotine-evoked currents as observed with ACh, revealing a shift in agonist effect that produced a large LS response. Both α4R336C and α4R487Q showed a shift from a monophasic, HS relationship to biphasic activation, with both variants gaining LS activation components. The size of the LS component was particularly large for α4R336C (see Figure 4 in McClure-Begley et al.18). Such an effect was not seen for α4P451L18 consistent with the lack of association with FTND for the P451L variant (Table 1).
