The α5 subunit does not form functional receptors when expressed alone, or co-expressed with a β subunit (Ramirez-Latorre et al. 1996), but when combined with an additional α subunit and either a β2 or β4 subunit it alters several pharmacological properties of the receptor in response to nicotine (Gerzanich et al. 1998; Tapia et al. 2007). The α5 variant D398N, in the region encoding the α5, α3, and β4 nAChR subunits, causes a change in the amino acid sequence and has been shown to reduce the response to epibatidine of (α4β2)2α5 nAChRs, a subtype important in mediating the effects of nicotine (Bierut et al. 2008). Kuryatov and others expressed this variant in X. laevis oocytes and observed that the α5 Asn 398 risk variant in (α4β2)2α5 nAChRs had lower Ca2+ permeability and greater short-term desensitization than the α5 Asp 398 variant when exposed to nicotine. The results suggest that this variation in the α5 subtype might reduce nicotinic signaling, potentially resulting in heavier smoking (Kuryatov et al. 2011).
