The Drosophila ERG channel seizure plays a role in the neuronal homeostatic stress response
The Drosophila ERG channel seizure plays a role in the neuronal homeostatic stress response
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DOI：
10.1371/journal.pgen.1008288
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发表时间：
2019-08-01
期刊：
影响因子：
4.5
通讯作者：
Ben-Shahar, Yehuda
中科院分区：
文献类型：
--
作者：
Hill, Alexis S.;Jain, Poorva;Ben-Shahar, Yehuda
神经生理学对影响兴奋性的急性应激源特别敏感，其中许多应激源可引发癫痫发作。尽管内在的神经元稳态在维持整个神经系统的稳健性及其对压力源的抵抗力方面起着重要作用，但这些过程背后的特定遗传和分子机制尚未得到很好的理解。在这里，我们在果蝇中使用了一种反向遗传方法来测试特定电压门控离子通道有助于神经元稳态、稳健性和抗逆性的假设。我们发现，与哺乳动物ERG通道家族同源的电压门控钾通道癫痫（sei）的活性对于保护苍蝇免受急性热诱发癫痫发作至关重要。尽管sei在神经系统中广泛表达，但我们的数据表明，它对机体对急性环境应激的稳健性的影响主要是通过其在兴奋性神经元、章鱼胺能系统以及神经堆鞘层和神经周围胶质细胞中的作用来介导的。此外，我们的研究表明，人类ERG通道（hERG）的突变，主要与心脏长QT综合征（LQTS）有关，也可能通过心血管无关的神经源性途径导致LQTS患者癫痫发作的高发生率。神经元对各种环境压力源非常敏感，包括环境温度的快速变化。为了缓冲环境压力，许多动物已经进化出多种生理机制来保护神经活动免受急性和慢性应激源的影响。这些保障措施的失败常常导致过度兴奋、发作性癫痫和慢性癫痫。然而，尽管癫痫发作和相关综合征很常见，但其潜在的分子和遗传因素，以及它们与环境触发因素的相互作用，大多仍然未知。在这里，我们发现，在果蝇中，ERG电压门控钾通道发作（sei）的突变也增加了发作的易感性，这是人类hERG通道的同源物，以前曾被认为与心脏长qt综合征有关。我们证明除了心脏表达外，sei通道在神经系统中也广泛表达。在神经元中，sei通道在轴突突起中丰富，并且在兴奋性和八胺能调节神经元以及非神经元胶质中特别需要，以维持对热诱发癫痫发作的机体抵抗。因此，我们的工作表明，先前报道的hERG突变个体癫痫易感性的增加可能与其神经元作用有关，而与心脏功能无关。
Neuronal physiology is particularly sensitive to acute stressors that affect excitability, many of which can trigger seizures and epilepsies. Although intrinsic neuronal homeostasis plays an important role in maintaining overall nervous system robustness and its resistance to stressors, the specific genetic and molecular mechanisms that underlie these processes are not well understood. Here we used a reverse genetic approach in Drosophila to test the hypothesis that specific voltage-gated ion channels contribute to neuronal homeostasis, robustness, and stress resistance. We found that the activity of the voltage-gated potassium channel seizure (sei), an ortholog of the mammalian ERG channel family, is essential for protecting flies from acute heat-induced seizures. Although sei is broadly expressed in the nervous system, our data indicate that its impact on the organismal robustness to acute environmental stress is primarily mediated via its action in excitatory neurons, the octopaminergic system, as well as neuropile ensheathing and perineurial glia. Furthermore, our studies suggest that human mutations in the human ERG channel (hERG), which have been primarily implicated in the cardiac Long QT Syndrome (LQTS), may also contribute to the high incidence of seizures in LQTS patients via a cardiovascular-independent neurogenic pathway.Author summary Neurons are extremely sensitive to diverse environmental stressors, including rapid changes in the ambient temperature. To buffer environmental stress, many animals have evolved diverse physiological mechanisms to protect neuronal activity from acute and chronic stressors. Failures of these safeguards often lead to hyperexcitability, episodic seizures, and chronic epilepsy. However, although seizures and related syndromes are common, their underlying molecular and genetic factors, and their interactions with environmental triggers, remain mostly unknown. Here, we show that in the fruit fly, mutations in the ERG voltage-gated potassium channel seizure (sei), an ortholog of the human hERG channel that has been previously implicated in the cardiac Long-QT syndrome, also increases seizure susceptibility. We demonstrate that in addition to its cardiac expression, the sei channel is broadly expressed in the nervous system. In neurons, sei channels are enriched in axonal projections, and are specifically required in excitatory and octopaminergic modulatory neurons, as well as the non-neuronal glia, for maintaining organismal resistance to heat-induced seizures. Thus, our work indicates that the previously reported increase in seizure susceptibility in individuals with mutations in hERG is possibly related to its neuronal action, independent of its cardiac functions.