Lipid environment modulates the development of acute tolerance to ethanol in Caenorhabditis elegans.
Lipid environment modulates the development of acute tolerance to ethanol in Caenorhabditis elegans.
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脂质环境调节了秀丽隐杆线虫中对乙醇的急性耐受性的发展。
DOI：
10.1371/journal.pone.0035192
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Davies AG
中科院分区：
文献类型：
--
作者：
Bettinger JC;Leung K;Bolling MH;Goldsmith AD;Davies AG
在神经元水平上对药物的耐受性的发展反映了一种稳态机制，神经元通过这种机制对外部刺激对其功能的扰动作出反应。对乙醇的急性功能性耐受（AFT）是一种快速的代偿反应，在单次给药过程中发展，尽管药物持续存在，但神经元功能正常化。我们进行了一个遗传筛选，以确定所需的基因的发展急性功能耐受乙醇的线虫C。优雅我们确定了影响已知通过脂肪酶LIPS-7调节三酰甘油（TAG）水平的遗传途径中的多个基因的突变，表明TAG在耐受性的发展中具有重要作用。基因操作的嘴唇-7表达，向上或向下，产生相反的效果对乙醇的敏感性和AFT的发展速度。此外，通过环境操作降低胆固醇水平反映了TAG水平降低的影响。最后，我们发现TAG脂肪酶LIPS-7水平的遗传改变可以改变乙醇诱导离子通道SLO-1（电压和钙敏感性BK通道）功能获得性突变的表型。这项研究表明，脂质环境调节神经元对乙醇的反应，包括初始敏感性和急性耐受性的发展。这些结果为酒精依赖的研究提供了新的见解，并提出了一个模型，其中TAG水平通过改变乙醇对膜蛋白的作用对AFT的发展非常重要。
The development of tolerance to a drug at the level of the neuron reflects a homeostatic mechanism by which neurons respond to perturbations of their function by external stimuli. Acute functional tolerance (AFT) to ethanol is a fast compensatory response that develops within a single drug session and normalizes neuronal function despite the continued presence of the drug. We performed a genetic screen to identify genes required for the development of acute functional tolerance to ethanol in the nematode C. elegans. We identified mutations affecting multiple genes in a genetic pathway known to regulate levels of triacylglycerols (TAGs) via the lipase LIPS-7, indicating that there is an important role for TAGs in the development of tolerance. Genetic manipulation of lips-7 expression, up or down, produced opposing effects on ethanol sensitivity and on the rate of development of AFT. Further, decreasing cholesterol levels through environmental manipulation mirrored the effects of decreased TAG levels. Finally, we found that genetic alterations in the levels of the TAG lipase LIPS-7 can modify the phenotype of gain-of-function mutations in the ethanol-inducible ion channel SLO-1, the voltage- and calcium-sensitive BK channel. This study demonstrates that the lipid milieu modulates neuronal responses to ethanol that include initial sensitivity and the development of acute tolerance. These results lend new insight into studies of alcohol dependence, and suggest a model in which TAG levels are important for the development of AFT through alterations of the action of ethanol on membrane proteins.
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DOI：
10.1111/j.1530-0277.2011.01479.x
发表时间：
2011-08-01
影响因子：
3.2
作者：
Ghare, Smita;Patil, Madhuvanti;Joshi-Barve, Swati
通讯作者：
Joshi-Barve, Swati
影响因子：
21.3
作者：
Prior, IA;Harding, A;Hancock, JF
通讯作者：
Hancock, JF
影响因子：
3.8
作者：
Bukiya, Anna N.;Belani, Jitendra D.;Dopico, Alex M.
通讯作者：
Dopico, Alex M.
影响因子：
3.3
作者：
Glodowski, Doreen R.;Chen, Carlos Chih-Hsiung;Rongo, Christopher
通讯作者：
Rongo, Christopher
影响因子：
6.5
作者：
Merris, M;Wadsworth, WG;Lenard, J
通讯作者：
Lenard, J