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Altering the Relative Abundance of GABA A Receptor Subunits Changes GABA‐ and Ethanol‐Responses in Xenopus Oocytes
Author(s) -
Hurley Joyce H.,
Ballard Carrie J.,
Edenberg Howard J.
Publication year - 2009
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/j.1530-0277.2009.00930.x
Subject(s) - xenopus , ethanol , gabaa receptor , chemistry , abundance (ecology) , receptor , protein subunit , microbiology and biotechnology , biology , biochemistry , ecology , gene
Background: Variations in GABRA2 and GABRG3 , genes encoding the α2 and γ3 subunits of the pentameric GABA A receptor, are associated with the risk of developing alcoholism in adults, conduct disorder at younger ages, and with differences in electroencephalographic power in the β frequency range. The SNPs associated with alcoholism did not alter the coding of these genes, and extensive DNA sequencing of GABRA2 did not find coding changes in the high‐risk haplotypes. Therefore, we hypothesize that the associations arise from differences in gene expression. Methods: Here we report studies in Xenopus oocytes to examine the functional effects of altering the relative abundance of these 2 receptor subunits on GABA current and response to ethanol, as a model of potential effects of regulatory differences. Results: When human α2β2γ3 subunits are co‐expressed, increasing the amount of the α2 subunit mRNA increased GABA current; in contrast, increasing the amount of the γ3 subunit decreased GABA currents. Acute ethanol treatment of oocytes injected with a 1:1:1 or 2:2:1 ratio of α2:β2:γ3 subunit mRNAs resulted in significant potentiation of GABA currents, whereas ethanol inhibited GABA currents in cells injected with a 6:2:1 ratio. Overnight treatment with ethanol significantly reduced GABA currents in a manner dependent on the ratio of subunits. Conclusions: These studies demonstrate that changes in relative expression of GABA A receptor subunits alter the response of the resulting channels to GABA and to ethanol.