Role of the DSC1 channel in regulating neuronal excitability in Drosophila melanogaster: extending nervous system stability under stress.
Role of the DSC1 channel in regulating neuronal excitability in Drosophila melanogaster: extending nervous system stability under stress.
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DOI：
10.1371/journal.pgen.1003327
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Dong K
中科院分区：
文献类型：
--
作者：
Zhang T;Wang Z;Wang L;Luo N;Jiang L;Liu Z;Wu CF;Dong K
电压门控离子通道对于神经元和其他可兴奋细胞的电信号传导至关重要。其中，电压门控钠通道和钙通道是四结构域蛋白质，离子选择性受到这些通道孔区域中氨基酸环的强烈影响。钠通道包含 DEKA 基序（即，分别位于结构域 I、II、III 和 IV 的孔位置处的氨基酸 D、E、K 和 A），而电压门控钙通道包含 EEEE 基序（即，在所有四个位置处的酸性残基 E）。最近，在多种无脊椎动物中发现了包含中间 DEEA 基序的新型离子通道蛋白家族。然而，这种新的离子通道家族在动物生物学中的生理作用仍然难以捉摸。果蝇中的 DSC1 是这个新离子通道家族的原型。在这项研究中，我们通过同源重组使用末端基因靶向生成了两个 DSC1 敲除系。 DSC1 突变果蝇表现出嗅觉受损和明显的跳跃表型，这种表型因热休克和饥饿而加剧。对巨纤维系统 (GFS)（一个明确的中枢神经回路）的电生理学分析表明，DSC1 突变体的 GFS 活动发生了改变，包括 GFS 跟随重复刺激的能力（即跟随能力）以及对热休克、饥饿和拟除虫菊酯杀虫剂的反应。这些结果揭示了 DSC1 通道在调节神经回路稳定性方面的重要作用，特别是在环境压力下，可能是通过维持突触传递的可持续性来实现的。电压门控钠通道和钙通道是四域蛋白，对于神经元和其他可兴奋细胞的电信号传导至关重要。最近的基因组和功能分析揭示了从海葵到昆虫的各种无脊椎动物中存在一个新的四结构域 Ca2+ 选择性阳离子通道家族。这些通道的氨基酸序列和门控特性似乎介于钠通道和钙通道之间；因此，这些通道可能是钠通道和钙通道之间重要的进化联系。尽管这个阳离子通道家族具有有趣的性质，但它们在动物生理学中的作用仍然是神秘的。在这项研究中，我们利用果蝇（Drosophila melanogaster）的遗传易驯性，研究了这种称为 DSC1 的通道在该模型昆虫中的生理作用。我们生成了两条 DSC1 敲除系并进行了行为和电生理学分析。我们的结果表明，DSC1 通道有助于神经元兴奋性调节，并在保持神经系统功能稳定性以应对环境应激（包括热休克和饥饿）方面发挥着独特的作用。有趣的是，DSC1 基因敲除果蝇也更容易受到拟除虫菊酯杀虫剂的影响，而拟除虫菊酯杀虫剂在全球范围内被用作对抗携带疟疾的蚊子的主要武器。
Voltage-gated ion channels are essential for electrical signaling in neurons and other excitable cells. Among them, voltage-gated sodium and calcium channels are four-domain proteins, and ion selectivity is strongly influenced by a ring of amino acids in the pore regions of these channels. Sodium channels contain a DEKA motif (i.e., amino acids D, E, K, and A at the pore positions of domains I, II, III, and IV, respectively), whereas voltage-gated calcium channels contain an EEEE motif (i.e., acidic residues, E, at all four positions). Recently, a novel family of ion channel proteins that contain an intermediate DEEA motif has been found in a variety of invertebrate species. However, the physiological role of this new family of ion channels in animal biology remains elusive. DSC1 in Drosophila melanogaster is a prototype of this new family of ion channels. In this study, we generated two DSC1 knockout lines using ends-out gene targeting via homologous recombination. DSC1 mutant flies exhibited impaired olfaction and a distinct jumpy phenotype that is intensified by heat shock and starvation. Electrophysiological analysis of the giant fiber system (GFS), a well-defined central neural circuit, revealed that DSC1 mutants are altered in the activities of the GFS, including the ability of the GFS to follow repetitive stimulation (i.e., following ability) and response to heat shock, starvation, and pyrethroid insecticides. These results reveal an important role of the DSC1 channel in modulating the stability of neural circuits, particularly under environmental stresses, likely by maintaining the sustainability of synaptic transmission. Voltage-gated sodium and calcium channels are four-domain proteins that are essential for electrical signaling in neurons and other excitable cells. Recent genomic and functional analyses reveal a novel family of four-domain, Ca2+-selective cation channels in a variety of invertebrates, from sea anemones to insects. The amino acid sequences and gating properties of these channels appear to be intermediate between sodium and calcium channels; as such, these channels could potentially be an important evolutionary link between sodium and calcium channels. Despite the intriguing nature of this family of cation channels, their role in animal physiology remains mysterious. In this study, taking advantage of the genetic tractability of the fruit fly, Drosophila melanogaster, we examined the physiological role of such a channel, called DSC1, in this model insect. We generated two DSC1 knockout lines and conducted behavioral and electrophysiological analyses. Our results show that the DSC1 channel contributes to neuronal excitability regulation and plays a unique role in retaining stability of the nervous system function in response to environmental stresses, including heat shock and starvation. Interestingly, the DSC1 knockout flies were also more susceptible to pyrethroid insecticides, which are used globally as a major weapon against the malaria-carrying mosquitoes.
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DOI：
10.1073/pnas.1106363108
发表时间：
2011-05-31
影响因子：
11.1
作者：
Liebeskind, Benjamin J.;Hillis, David M.;Zakon, Harold H.
通讯作者：
Zakon, Harold H.
DOI：
10.1073/pnas.0535280100
发表时间：
2003-03-04
影响因子：
11.1
作者：
Gong, WJ;Golic, KG
通讯作者：
Golic, KG
影响因子：
2.5
作者：
TANOUYE, MA;WYMAN, RJ
通讯作者：
WYMAN, RJ
DOI：
10.1007/bf00195964
发表时间：
1992-08-01
影响因子：
2.1
作者：
ENGEL, JE;WU, CF
通讯作者：
WU, CF
影响因子：
8.8
作者：
Gur Barzilai M;Reitzel AM;Kraus JE;Gordon D;Technau U;Gurevitz M;Moran Y
通讯作者：
Moran Y