Animal experiments have demonstrated that activation of α4β2 nAChRs is involved in the development of ND (5,8,9). Therefore, current understanding is consistent with the notion that nonsynonymous rare variants s in the cytoplasmic loop of the α4 subunit may have a protective effect against ND. Evaluation of the role of these rare variants in the α4 subunit in nAChR function by making point mutations in the functional consequence using in vitro or in vivo models will help identify the structure-activity changes resulting from these changes.
