KCNQ channels show conserved ethanol block and function in ethanol behaviour.
KCNQ channels show conserved ethanol block and function in ethanol behaviour.
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DOI：
10.1371/journal.pone.0050279
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Hodge JJ
中科院分区：
文献类型：
--
作者：
Cavaliere S;Gillespie JM;Hodge JJ
在人类中，KCNQ2/3通道形成一个调节神经元兴奋性的m电流，这些通道的突变引起良性新生儿家族性惊厥。m电流在联想记忆的神经可塑性机制和对乙醇的反应中很重要，KCNQ控制乙醇暴露后多巴胺的释放。我们发现，dKCNQ在神经系统中广泛表达，神经元KCNQ的靶向减少会增加神经兴奋性，而KCNQ的过表达会降低兴奋性和钙信号传导，这与KCNQ在哺乳动物神经元中调节静息膜电位和神经释放一致。我们发现果蝇的单个KCNQ通道（dKCNQ）与神经元KCNQ2/3具有相似的电生理特性，包括对乙醇阻断的保守急性敏感性，其中果蝇通道（IC50 = 19.8 mM）比其哺乳动物通道（IC50 = 42.1 mM）更敏感。这表明KCNQ在酒精行为中的作用可以首次通过果蝇来确定。我们提供的证据表明，KCNQ功能的丧失增加了果蝇对乙醇镇静作用的敏感性和耐受性。通过热激活TRP通道或KCNQ-RNAi表达急性激活多巴胺能神经元产生乙醇超敏反应，这表明两者都通过一种共同的机制起作用，包括膜去极化和增加多巴胺信号导致乙醇镇静。
In humans, KCNQ2/3 channels form an M-current that regulates neuronal excitability, with mutations in these channels causing benign neonatal familial convulsions. The M-current is important in mechanisms of neural plasticity underlying associative memory and in the response to ethanol, with KCNQ controlling the release of dopamine after ethanol exposure. We show that dKCNQ is broadly expressed in the nervous system, with targeted reduction in neuronal KCNQ increasing neural excitability and KCNQ overexpression decreasing excitability and calcium signalling, consistent with KCNQ regulating the resting membrane potential and neural release as in mammalian neurons. We show that the single KCNQ channel in Drosophila (dKCNQ) has similar electrophysiological properties to neuronal KCNQ2/3, including conserved acute sensitivity to ethanol block, with the fly channel (IC50 = 19.8 mM) being more sensitive than its mammalian ortholog (IC50 = 42.1 mM). This suggests that the role of KCNQ in alcohol behaviour can be determined for the first time by using Drosophila. We present evidence that loss of KCNQ function in Drosophila increased sensitivity and tolerance to the sedative effects of ethanol. Acute activation of dopaminergic neurons by heat-activated TRP channel or KCNQ-RNAi expression produced ethanol hypersensitivity, suggesting that both act via a common mechanism involving membrane depolarisation and increased dopamine signalling leading to ethanol sedation.
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影响因子：
25
作者：
Lewohl, JM;Wilson, WR;Harris, RA
通讯作者：
Harris, RA
影响因子：
3.4
作者：
Mezler, M;Müller, T;Raming, K
通讯作者：
Raming, K
影响因子：
3.7
作者：
Kong EC;Woo K;Li H;Lebestky T;Mayer N;Sniffen MR;Heberlein U;Bainton RJ;Hirsh J;Wolf FW
通讯作者：
Wolf FW
影响因子：
5.3
作者：
Kapfhamer, David;Berger, Karen H.;Heberlein, Ulrike
通讯作者：
Heberlein, Ulrike
影响因子：
12.3
作者：
Morozova, Tatiana V.;Anholt, Robert R. H.;Mackay, Trudy Fc
通讯作者：
Mackay, Trudy Fc