Functional expression of an alpha 5 beta 2 nicotinic acetylcholine receptor

The alpha5 subunit belongs to the family of nicotinic acetylcholine receptors (nAChRs), which are ligand-gated, cation selective channels. The alpha5 is predominantly expressed in limbic and autonomic regions. Although alpha5 subunits are apparently associated with beta2 or beta4 subunits in neurons, no functional expression has been reported to date. It has, therefore, been suggested that these subunits merely act as accessory subunits. Here. we report for the first time expression of functional nAChRs with only alpha5 combined with beta2 or beta4 subunits. Functionality of the human alpha5 was observed only when the cDNA encoding for this subunit contained its adjacent untranslated region (UTR). When expressed in Xenopus oocytes alpha5 containing receptors (alpha5beta2 or alpha5beta4) displayed robust currents in response to ACh and were typically in the ?A range. The alpha5beta2 nAChR displayed a high sensitivity to ACh with an EC50 of 1.63 ± 0.15 ?M which is about 10-fold more sensitive than the major brain alpha4beta2 receptors. These receptors also displayed a high sensitivity to nicotine with an EC50 of 0.58 ± 0.17 ?M. Altogether these data demonstrate that functional receptors can be obtained with a binary combination of alpha5 with a beta subunit and that these receptors may play an important physiological role both in the central and peripheral nervous system. The high degree of correlation between smoking and cancer in human with alpha5 and its non-synonymous single nucleotide polymorphism further calls for a better understanding of the functional role of this subunit. These data open new avenues for the screening of the physiological properties of alpha5 containing nAChRs.