The α5 subunit regulates the expression and function of α4*-containing neuronal nicotinic acetylcholine receptors in the ventral-tegmental area.
The α5 subunit regulates the expression and function of α4*-containing neuronal nicotinic acetylcholine receptors in the ventral-tegmental area.
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DOI：
10.1371/journal.pone.0068300
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Bartlett SE
中科院分区：
文献类型：
--
作者：
Chatterjee S;Santos N;Holgate J;Haass-Koffler CL;Hopf FW;Kharazia V;Lester H;Bonci A;Bartlett SE
人类遗传关联研究表明，神经元尼古丁受体(NAChR)α5亚单位的基因变异影响酒精和尼古丁依赖。α5亚基是促进α4*nAChRs体外组装的辅助亚基。然而，目前还不清楚这种情况是否发生在大脑中，因为几乎没有研究工具来充分解决这个问题。由于含有α4*的nAChRs在腹侧被盖区高表达，我们研究了α5在腹侧被盖区含有α4*的nAChRs中的分子、功能和药理作用。我们利用转基因小鼠α5+/+(α4YFP)和α5-/-(α4YFP)，可以直接观察和测量α4-YFP的表达以及存在(α5+/+)和不存在α5(-/-)亚基的影响，因为检测α4*亚基的抗体是非特异性的。我们进行了电压钳电生理实验，以研究VTA多巴胺能神经元的基础烟碱电流。我们发现，在α5亚基存在的情况下，α4亚基在视网膜区的总表达显著增加60%。此外，α5亚基增强了基础nAChR电流，提示α4*nAChRs的表达增加可能是在细胞表面。虽然α5亚单位的存在钝化了尼古丁暴露后nAChRs的脱敏，但它不改变VTA多巴胺能神经元的乙醇增强量。我们的数据表明，α5亚单位在维持α4*的nAChRs表达和调节VTA多巴胺能神经元的烟碱电流方面起着重要的调节作用。此外，VTA多巴胺能神经元上的α5α4*nAChR调节尼古丁的电流效应，但不能调节乙醇的效应。综上所述，这些数据表明，α5亚基对于控制一组含有α4*的nAChRs在VTA中的表达和功能起着关键作用。
Human genetic association studies have shown gene variants in the α5 subunit of the neuronal nicotinic receptor (nAChR) influence both ethanol and nicotine dependence. The α5 subunit is an accessory subunit that facilitates α4* nAChRs assembly in vitro. However, it is unknown whether this occurs in the brain, as there are few research tools to adequately address this question. As the α4*-containing nAChRs are highly expressed in the ventral tegmental area (VTA) we assessed the molecular, functional and pharmacological roles of α5 in α4*-containing nAChRs in the VTA. We utilized transgenic mice α5+/+(α4YFP) and α5-/-(α4YFP) that allow the direct visualization and measurement of α4-YFP expression and the effect of the presence (α5+/+) and absence of α5 (-/-) subunit, as the antibodies for detecting the α4* subunits of the nAChR are not specific. We performed voltage clamp electrophysiological experiments to study baseline nicotinic currents in VTA dopaminergic neurons. We show that in the presence of the α5 subunit, the overall expression of α4 subunit is increased significantly by 60% in the VTA. Furthermore, the α5 subunit strengthens baseline nAChR currents, suggesting the increased expression of α4* nAChRs to be likely on the cell surface. While the presence of the α5 subunit blunts the desensitization of nAChRs following nicotine exposure, it does not alter the amount of ethanol potentiation of VTA dopaminergic neurons. Our data demonstrates a major regulatory role for the α5 subunit in both the maintenance of α4*-containing nAChRs expression and in modulating nicotinic currents in VTA dopaminergic neurons. Additionally, the α5α4* nAChR in VTA dopaminergic neurons regulates the effect of nicotine but not ethanol on currents. Together, the data suggest that the α5 subunit is critical for controlling the expression and functional role of a population of α4*-containing nAChRs in the VTA.
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DOI：
10.1523/jneurosci.2258-10.2010
发表时间：
2010-07-07
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Bailey CD;De Biasi M;Fletcher PJ;Lambe EK
通讯作者：
Lambe EK
DOI：
10.1111/j.1601-183x.2009.00476.x
发表时间：
2009-06
期刊：
Genes, brain, and behavior
影响因子：
--
作者：
Gangitano D;Salas R;Teng Y;Perez E;De Biasi M
通讯作者：
De Biasi M
影响因子：
4.7
作者：
Brown, Robert W. B.;Collins, Allan C.;Whiteaker, Paul
通讯作者：
Whiteaker, Paul
影响因子：
5
作者：
Ericson, M;Molander, A;Söderpalm, B
通讯作者：
Söderpalm, B
DOI：
10.1097/00000374-199911000-00019
发表时间：
1999-11-01
影响因子：
3.2
作者：
Brodie, MS;Pesold, C;Appel, SB
通讯作者：
Appel, SB