Vol. 62, Issue 2, 334-342, August 2002

A Polymorphism in the Mouse Neuronal 4 Nicotinic Receptor Subunit Results in An Alteration in Receptor Function

Peter Dobelis, Michael J. Marks, Paul Whiteaker, Seth A. Balogh, Allan C. Collins, and Jerry A. Stitzel

Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado (P.D., M.J.M., P.W., S.A.B., A.C.C.); Department of Pharmacology, University of Colorado Health Sciences Center, Denver, Colorado (P.D.); and Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (J.A.S.)

Nicotine-stimulated ⁸⁶Rb⁺ efflux and [³H]cytisine binding, both of which seem to measure the nicotinic acetylcholine receptor, composed of 4 and 2 subunits, were assessed in eight brain regions obtained from 14 inbred mouse strains. The potential role of a single nucleotide polymorphism (SNP) in the nicotinic receptor 4 subunit gene (Chrna4) on nicotinic receptor binding and function in mice was also evaluated. This SNP leads to an alanine-to-threonine variation at amino acid position 529 of the nascent 4 subunit polypeptide. Both nicotine-stimulated ⁸⁶Rb⁺ efflux and [³H]cytisine binding were found to vary across brain regions and among mouse strains. Variability in nicotine-stimulated ⁸⁶Rb⁺ efflux was positively correlated (r > 0.9) within each strain with the number of [³H]cytisine binding sites. However, the number of [³H]cytisine binding sites was not correlated with nicotine-stimulated ⁸⁶Rb⁺ efflux across mouse strains. In contrast, the Chrna4 polymorphism was associated with receptor function across mouse strains: ⁸⁶Rb⁺ efflux was greater in seven of the eight brain regions studied in those mouse strains that carry the Ala-529 variant of Chrna4. The Chrna4 SNP did not seem to influence the number of [³H]cytisine binding sites across mouse strains. These data indicate that inbred mouse strains exhibit differences in receptor function that cannot be attributed to variation in receptor expression but may be explained, at least in part, by the missense polymorphism in the 4 subunit.