HSP-4 endoplasmic reticulum (ER) stress pathway is not activated in a C. elegans model of ethanol intoxication and withdrawal.
HSP-4 endoplasmic reticulum (ER) stress pathway is not activated in a C. elegans model of ethanol intoxication and withdrawal.
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在乙醇中毒和戒断的秀丽隐杆线虫模型中，HSP-4 内质网 (ER) 应激通路未激活。
DOI：
10.1007/s10158-012-0136-7
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发表时间：
2012
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通讯作者：
Ient B
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作者：
Ient B
在250-350 mM范围内的乙醇浓度下，线虫的急性和慢性暴露会引起不同的行为。先前的遗传分析强调了这些效应的特定神经生物学底物。然而，乙醇也可能引起细胞应激反应，这可能有助于乙醇诱导的行为库。在这里，我们研究了乙醇对细胞应激途径的一个重要分支的影响，该途径来自内质网（ER），以响应包括热休克和导致蛋白质错误折叠的化学或遗传扰动在内的几种条件。HSP-4是一种热休克蛋白，是哺乳动物BiP的同源物。它是ER应激反应的关键上游组分。因此，我们使用aC。elegansheat休克蛋白突变体hsp-4和携带转录报告基因Phsp-4：：gfp的菌株，以测试ER在慢性乙醇调节后的作用。我们没有发现明显的ER反应的证据，在急性或长期暴露于浓度的乙醇，导致定义的乙醇诱导的行为。此外，尽管thsp-4被衣霉素强烈诱导，但C. elegansto低剂量衣霉素随后乙醇不足以诱导累加ER应激反应。行为学分析表明anhsp-4突变体与野生型相比对酒精中毒和戒断的敏感性没有差异。有一个明确的先例，ER应激途径的意义，特别是在临床条件下与高剂量的酒精消费的毒性或病理影响。本试验中所用的乙醇浓度为C. elegans研究等同于在慢性酒精依赖患者中测量的最高血液酒精水平。综上所述，这些观察结果表明，经典的ER应激途径在C。elegansis相对难诱导乙醇。
Acute and chronic exposure ofCaenorhabditis elegansto concentrations of ethanol in the range 250–350 mM elicits distinct behaviours. Previous genetic analysis highlights specific neurobiological substrates for these effects. However, ethanol may also elicit cellular stress responses which may contribute to the repertoire of ethanol-induced behaviours. Here, we have studied the effect of ethanol on an important arm of the cellular stress pathways, which emanates from the endoplasmic reticulum (ER) in response to several conditions including heat shock and chemical or genetic perturbations that lead to protein misfolding. HSP-4 is a heat shock protein and homologue of mammalian BiP. It is a pivotal upstream component of the ER stress response. Therefore, we used aC. elegansheat shock protein mutant,hsp-4, and a strain carrying a transcriptional reporter,Phsp-4::gfp, to test the role of the ER following chronic ethanol conditioning. We found no evidence for an overt ER response during acute or prolonged exposure to concentrations of ethanol that lead to defined ethanol-induced behaviours. Furthermore, whilsthsp-4was strongly induced by tunicamycin, pre-exposure ofC. elegansto low doses of tunicamycin followed by ethanol was not sufficient to induce an additive ER stress response. Behavioural analysis of anhsp-4mutant indicated no difference compared to wild type in susceptibility to ethanol intoxication and withdrawal. There is a clear precedent for a significance of ER stress pathways particularly in clinical conditions associated with toxic or pathological effects of high doses of alcohol consumption. The concentrations of ethanol used in thisC. elegansstudy equate to the highest blood alcohol levels measured in patients with chronic alcohol dependency. Taken together, these observations imply that the classic ER stress pathway inC. elegansis relatively refractory to induction by ethanol.