Journal
MOLECULAR PHARMACOLOGY
Volume 62, Issue 2, Pages 334-342Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/mol.62.2.334
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Funding
- NIAAA NIH HHS [AA11156] Funding Source: Medline
- NIDA NIH HHS [DA14369, DA00197, DA10156] Funding Source: Medline
- NIMH NIH HHS [MH61617] Funding Source: Medline
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Nicotine-stimulated Rb-86(+) efflux and [H-3] cytisine binding, both of which seem to measure the nicotinic acetylcholine receptor, composed of alpha4 and beta2 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 alpha4 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 alpha4 subunit polypeptide. Both nicotine-stimulated Rb-86(+) efflux and [H-3] cytisine binding were found to vary across brain regions and among mouse strains. Variability in nicotine-stimulated Rb-86(+) efflux was positively correlated (r > 0.9) within each strain with the number of [H-3] cytisine binding sites. However, the number of [H-3] cytisine binding sites was not correlated with nicotine-stimulated Rb-86(+) efflux across mouse strains. In contrast, the Chrna4 polymorphism was associated with receptor function across mouse strains: Rb-86(+) 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 [H-3] 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 alpha4 subunit.
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