Nitric oxide-mediated posttranslational modifications control neurotransmitter release by modulating complexin farnesylation and enhancing its clamping ability.
Nitric oxide-mediated posttranslational modifications control neurotransmitter release by modulating complexin farnesylation and enhancing its clamping ability.
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DOI：
10.1371/journal.pbio.2003611
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发表时间：
2018-04
期刊：
影响因子：
9.8
通讯作者：
Steinert JR
中科院分区：
文献类型：
--
作者：
Robinson SW;Bourgognon JM;Spiers JG;Breda C;Campesan S;Butcher A;Mallucci GR;Dinsdale D;Morone N;Mistry R;Smith TM;Guerra-Martin M;Challiss RAJ;Giorgini F;Steinert JR
一氧化氮（NO）调节神经元功能，因此对调节神经元通讯至关重要。NO调节蛋白质功能和相互作用的机制包括翻译后修饰（PTMs），如s -亚硝基化。重要的是，s -亚硝基化和戊酰化之间的交叉信号传导可能具有重要的调控潜力。然而，确切的蛋白质靶点和导致的功能变化仍然难以捉摸。在这里，我们探讨了no依赖性PTMs和法尼化在突触传递中的作用。我们发现NO以不依赖cgmp的方式损害果蝇神经肌肉接点（NMJ）的突触功能。NO抑制释放并减小可利用囊泡池的大小，这一作用被谷胱甘肽（GSH）逆转，并被GSH生成和去亚硝基化谷氨酸-半胱氨酸连接酶和s -亚硝基-谷胱甘肽还原酶活性的基因上调所阻断。氮能活性的增强导致融合钳蛋白复合物（cpx）的s -亚硝基化，改变了其与活性区（AZ）和可溶性n-乙基-马来酰亚胺敏感融合蛋白附着蛋白受体（SNARE）蛋白的膜结合和相互作用。此外，基因和药理学抑制法尼基化和亚硝基化模拟突变体cpx诱导相同的生理和定位表型引起的NO。总之，我们的数据为一种涉及s -亚硝基化的新型生理氮分子开关提供了证据，该开关可可逆地抑制法尼基化，从而增强cpx的网夹功能。这些数据说明了一种新的机制信号通路，通过该通路，法尼化调节可以微调突触释放。神经元彼此之间以及与其他组织（如肌肉）进行交流的一种方式，是在被称为突触的相互作用部位释放被称为神经递质的化合物。这种突触传递可以被释放神经元和接收神经元或肌肉细胞精细地调节。许多信号分子和途径参与神经递质释放。在本研究中，我们研究了其中一条通路及其在果蝇幼虫神经肌肉突触中调节神经递质释放的作用。这种调节涉及一氧化氮，一种自由扩散的反应分子，可以在运动神经元的活动中产生反应。几种神经元蛋白可以被一氧化氮修饰，我们的研究确定了一种调节神经递质释放的特定靶分子。这种蛋白质被称为络合蛋白，当一氧化氮水平升高时，它会发生翻译后修饰，改变其在突触的定位和功能，并调节神经传递。我们的发现可以解释神经元如何利用一氧化氮信号以活动依赖的方式调节通信。
Nitric oxide (NO) regulates neuronal function and thus is critical for tuning neuronal communication. Mechanisms by which NO modulates protein function and interaction include posttranslational modifications (PTMs) such as S-nitrosylation. Importantly, cross signaling between S-nitrosylation and prenylation can have major regulatory potential. However, the exact protein targets and resulting changes in function remain elusive. Here, we interrogated the role of NO-dependent PTMs and farnesylation in synaptic transmission. We found that NO compromises synaptic function at the Drosophila neuromuscular junction (NMJ) in a cGMP-independent manner. NO suppressed release and reduced the size of available vesicle pools, which was reversed by glutathione (GSH) and occluded by genetic up-regulation of GSH-generating and de-nitrosylating glutamate-cysteine-ligase and S-nitroso-glutathione reductase activities. Enhanced nitrergic activity led to S-nitrosylation of the fusion-clamp protein complexin (cpx) and altered its membrane association and interactions with active zone (AZ) and soluble N-ethyl-maleimide-sensitive fusion protein Attachment Protein Receptor (SNARE) proteins. Furthermore, genetic and pharmacological suppression of farnesylation and a nitrosylation mimetic mutant of cpx induced identical physiological and localization phenotypes as caused by NO. Together, our data provide evidence for a novel physiological nitrergic molecular switch involving S-nitrosylation, which reversibly suppresses farnesylation and thereby enhances the net-clamping function of cpx. These data illustrate a new mechanistic signaling pathway by which regulation of farnesylation can fine-tune synaptic release. One way neurons communicate with each other and with other tissues, such as muscle, is by releasing chemical compounds known as neurotransmitters at sites of interaction known as synapses. This synaptic transmission can be finely regulated by both the releasing neuron and the receiving neuron or muscle cell. Many signaling molecules and pathways are involved in neurotransmitter release. In this study, we have investigated one of such pathways and its role in modulating neurotransmitter release at the neuromuscular synapse of the larva of the fruit fly Drosophila melanogaster. This regulation involves nitric oxide, a freely diffusible reactive molecule that can be generated in response to activity in the motor neuron. Several neuronal proteins can be modified by nitric oxide, and our study identified a specific target molecule that regulates neurotransmitter release. This protein, called complexin, undergoes a posttranslational modification in response to increased levels of nitric oxide, changing its localization and function at the synapse and modulating neurotransmission. Our findings can explain how neurons may modulate communication in an activity-dependent manner utilizing nitric oxide signaling.
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影响因子：
16.2
作者：
Haustein MD;Kracun S;Lu XH;Shih T;Jackson-Weaver O;Tong X;Xu J;Yang XW;O'Dell TJ;Marvin JS;Ellisman MH;Bushong EA;Looger LL;Khakh BS
通讯作者：
Khakh BS
DOI：
10.1038/nrm3255
发表时间：
2011-12-22
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
5.3
作者：
Apolloni, A;Prior, IA;Hancock, JF
通讯作者：
Hancock, JF
DOI：
10.1073/pnas.1409311111
发表时间：
2014-07-15
影响因子：
11.1
作者：
Cho, Richard W.;Kuemmel, Daniel;Littleton, J. Troy
通讯作者：
Littleton, J. Troy
影响因子：
5.5
作者：
DODGE, FA;RAHAMIMO.R
通讯作者：
RAHAMIMO.R