Genome-wide studies have strongly associated a non-synonymous polymorphism (rs16969968) that changes the 398th amino acid in the nAChR Î±5 subunit from aspartic acid to asparagine (D398N), with greater risk for increased nicotine consumption. We have used a pentameric concatemer approach to express defined and consistent populations of Î±3Î²4Î±5 nAChR in Xenopus oocytes. Î±5(Asn-398; risk) variant incorporation reduces ACh-evoked function compared with inclusion of the common Î±5(Asp-398) variant without altering agonist or antagonist potencies. Unlinked Î±3, Î²4, and Î±5 subunits assemble to form a uniform nAChR population with pharmacological properties matching those of concatemeric Î±3Î²4* nAChRs. Î±5 subunit incorporation reduces Î±3Î²4* nAChR function after coinjection with unlinked Î±3 and Î²4 subunits but increases that of Î±3Î²4Î±5 versus Î±3Î²4-only concatemers. Î±5 subunit incorporation into Î±3Î²4* nAChR also alters the relative efficacies of competitive agonists and changes the potency of the non-competitive antagonist mecamylamine. Additional observations indicated that in the absence of Î±5 subunits, free Î±3 and Î²4 subunits form at least two further subtypes. The pharmacological profiles of these free subunit Î±3Î²4-only subtypes are dissimilar both to each other and to those of Î±3Î²4Î±5 nAChR. The Î±5 variant-induced change in Î±3Î²4Î±5 nAChR function may underlie some of the phenotypic changes associated with this polymorphism. Â© 2012 by The American Society for Biochemistry and Molecular Biology, Inc.
Journal of Biological Chemistry
Digital Object Identifier (DOI)
George, Andrew A.; Lucero, Linda M.; Damaj, M. Imad; Lukas, Ronald J.; Chen, Xiangning; and Whiteaker, Paul, "Function Of Human Î±3Î²4Î±5 Nicotinic Acetylcholine Receptors Is Reduced By The Î²5(D398N) Variant" (2012). Translational Neuroscience. 386.