Altered GABAA receptor expression and seizure threshold following acute ethanol challenge in mice lacking the RIIβ subunit of PKA.
Altered GABAA receptor expression and seizure threshold following acute ethanol challenge in mice lacking the RIIβ subunit of PKA.
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DOI：
10.1007/s11064-013-1167-0
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发表时间：
2014-06
影响因子：
4.4
通讯作者：
Morrow, A. Leslie
中科院分区：
文献类型：
--
作者：
Carlson, Stephen L.;O'Buckley, Todd K.;Thomas, Rhiannon;Thiele, Todd E.;Morrow, A. Leslie
乙醇引起GABAA受体运输和功能的病理变化。这些变化部分由蛋白激酶A（PKA）的乙醇活化介导。本研究在缺乏PKA调节RIIβ亚基的小鼠品系中，研究了基线和急性注射乙醇（3.5 g/kg IP）后GABAA α1和α4亚基和激酶锚定蛋白AKAP 150的表达，以及荷包牡丹碱诱导的癫痫发作阈值。在基线、注射乙醇或盐水后1小时或46小时收获全脑皮质，并进行分级分离和蛋白质印迹分析。与野生型（RII β +/+）同窝小鼠相比，敲除（RIIβ−/−）小鼠的PKA RIIα和GABAA α1和α4亚基基线水平相似，但AKAP 150缺乏。乙醇处理1 h后，RIIβ−/−小鼠P2部分的GABAA α1亚基水平降低，但RIIβ+/+小鼠没有，这是由突触部分α1表达降低引起的。P2部分中的GABAA α4亚基不受1 h乙醇的影响;然而，RIIβ+/+小鼠突触α4亚基表达增加，但RIIβ−/−小鼠没有，而RII β −/−小鼠突触外α4表达减少，但RIIβ+/+小鼠没有。最后，RIIβ基因敲除对荷包牡丹碱诱导的癫痫易感性具有保护作用。总之，结果表明PKA在调节GABAA受体亚基中具有不同的作用。PKA可能对乙醇诱导的突触α1和突触外α4受体的缺陷具有保护作用，但可能促进突触α4受体的增加。
Ethanol causes pathological changes in GABAA receptor trafficking and function. These changes are mediated in part by ethanol activation of protein kinase A (PKA). The current study investigated the expression of the GABAA α1 and α4 subunits and the kinase anchoring protein AKAP150, as well as bicuculline-induced seizure threshold, at baseline and following acute injection of ethanol (3.5 g/kg IP) in a mouse line lacking the regulatory RIIβ subunit of PKA. Whole cerebral cortices were harvested at baseline, 1 h, or 46 h following injection of ethanol or saline and subjected to fractionation and western blot analysis. Knockout (RIIβ−/−) mice had similar baseline levels of PKA RIIα and GABAA α1 and α4 subunits compared to wild type (RIIβ+/+) littermates, but had deficits in AKAP150. GABAA α1 subunit levels were decreased in the P2 fraction of RIIβ−/−, but not RIIβ+/+, mice following 1 h ethanol, an effect that was driven by decreased α1 expression in the synaptic fraction. GABAA α4 subunits in the P2 fraction were not affected by 1 h ethanol; however, synaptic α4 subunit expression was increased in RIIβ+/+, but not RIIβ−/− mice, while extrasynaptic α4 expression was decreased in RIIβ−/−, but not RIIβ+/+ mice. Finally, RIIβ knockout was protective against bicuculline-induced seizure susceptibility. Overall, the results suggest that PKA has differential roles in regulating GABAA receptor subunits. PKA may protect against ethanol-induced deficits in synaptic α1 and extrasynaptic α4 receptors, but may facilitate the increase of synaptic α4 receptors.
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DOI：
10.1097/01.alc.0000141809.53115.71
发表时间：
2004-10-01
影响因子：
3.2
作者：
Fee, JR;Sparta, DR;Thiele, TE
通讯作者：
Thiele, TE
DOI：
10.1111/j.1530-0277.2006.00096.x
发表时间：
2006-05-01
影响因子：
3.2
作者：
Ferraro, FM;Sparta, DR;Thiele, TE
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Thiele, TE
影响因子：
4.7
作者：
Harney, SC;Frenguelli, BG;Lambert, JJ
通讯作者：
Lambert, JJ
DOI：
10.1124/jpet.112.201954
发表时间：
2013-05-01
影响因子：
3.5
作者：
Carlson, Stephen L.;Kumar, Sandeep;Morrow, A. Leslie
通讯作者：
Morrow, A. Leslie
DOI：
10.1523/jneurosci.2490-12.2013
发表时间：
2013-02-20
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Herman MA;Contet C;Justice NJ;Vale W;Roberto M
通讯作者：
Roberto M