Role of Potassium Channel Gene Kcnj10 in Ethanol Preference in C57bl/6J and DBA/2J Mice

Background: Inwardly‐rectifying potassium channel protein Kir4.1 is encoded by Kcnj10 which maps to a quantitative trait locus on chromosome 1 for the voluntary alcohol consumption phenotype in mice. Kcnj10 brain expression differences have been established between ethanol‐preferring C57Bl/6J and ethanol‐avoiding BALB/cJ mice, but its differential expression in other tissues and strains have largely been overlooked. A nonsynonymous single nucleotide polymorphism exists between C57Bl/6J and ethanol‐avoiding DBA/2J mice which changes amino acid 262 from threonine (C57Bl/6J) to serine (DBA/2J). This Kcnj10 SNP and its expression may serve as valuable markers in predicting the ethanol preference phenotype in mice. Methods: The evolutionary divergence of the Kir gene family was characterized using phylogenetic analysis involving the 16 mouse Kir channels. Kcnj10 expression differences in the brain, liver, lung, heart, spleen, kidney, testes, and muscle of male C57Bl/6J and DBA/2J mice at different developmental stages were examined using semiquantitative RT‐PCR analysis. A SNP analysis was conducted to assess the association of Kcnj10 Thr262Ser SNP and the ethanol preference phenotype in F2 mice derived from the reciprocal crosses of the C57Bl/6J and DBA/2J strains. Results: Evolutionary analysis supports gene duplication and genetic recombination as likely sources of diversity within the Kir gene family. Semiquantitative RT‐PCR analysis revealed significantly higher Kcnj10 expression in the brain, spleen, and kidney of both strains when compared to other tissues from the same strain. There were no significant differences in tissue‐specific mRNA levels between strains except in the testes. Genotype distributions of the Kcnj10 Thr262Ser SNP were different between low‐ and high‐drinkers. A significant difference in the average ethanol preference level of each genotype was also observed. Conclusion: Our results suggest a role for Kcnj10 in ethanol preference determination in mice. However, further experiments are needed to establish if this association is due to the nonsynonymous SNP or other additional factors associated with Kcnj10.