Unc-51 controls active zone density and protein composition by downregulating ERK signaling.
Unc-51 controls active zone density and protein composition by downregulating ERK signaling.
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DOI：
10.1523/jneurosci.3848-08.2009
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发表时间：
2009-01-14
期刊：
影响因子：
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通讯作者：
Diantonio A
中科院分区：
文献类型：
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作者：
Wairkar YP;Toda H;Mochizuki H;Furukubo-Tokunaga K;Tomoda T;Diantonio A
有效的突触传递需要神经递质释放位点与突触后神经递质受体簇并置。递质在活性区释放，活性区由突触发育和功能所必需的蛋白质的大复合体组成。许多活性区蛋白已被确定，但很少有人知道的机制，确保每个活性区接收适当的蛋白质的补充。在这里，我们使用果蝇的遗传分析，以证明丝氨酸苏氨酸激酶Unc-51的行为在突触前运动神经元，以调节本地化的活性区蛋白Bruchpilot在每个突触的谷氨酸受体相反。在不存在Unc-51的情况下，许多谷氨酸受体簇与Bruchpilot不相关，超微结构分析表明，较少的活性区含有致密体T-条。除了这些异常突触的存在外，所有突触的密度也降低。这种突触密度的降低和异常的活动区成分与受损的诱发递质释放有关。在机制上，Unc-51抑制MAP激酶ERK的活性以促进突触发育。在unc-51突变体中，ERK活性增加导致突触密度降低和许多突触中Bruchpilot的缺失。因此，活化的ERK负调节突触形成，导致活性区的缺乏或活性区的形成而没有其适当的蛋白质补充。ERK活性的Unc-51依赖性抑制提供了突触特异性控制活性区蛋白组成和释放概率的潜在机制。
Efficient synaptic transmission requires the apposition of neurotransmitter release sites opposite clusters of postsynaptic neurotransmitter receptors. Transmitter is released at active zones, which are composed of a large complex of proteins necessary for synaptic development and function. Many active zone proteins have been identified, but little is known of the mechanisms that ensure that each active zone receives the proper complement of proteins. Here we use a genetic analysis in Drosophila to demonstrate that the serine threonine kinase Unc-51 acts in the presynaptic motoneuron to regulate the localization of the active zone protein Bruchpilot opposite to glutamate receptors at each synapse. In the absence of Unc-51, many glutamate receptor clusters are unapposed to Bruchpilot, and ultrastructural analysis demonstrates that fewer active zones contain dense body T-bars. In addition to the presence of these aberrant synapses, there is also a decrease in the density of all synapses. This decrease in synaptic density and abnormal active zone composition is associated with impaired evoked transmitter release. Mechanistically, Unc-51 inhibits the activity of the MAP kinase ERK to promote synaptic development. In the unc-51 mutant, increased ERK activity leads to the decrease in synaptic density and the absence of Bruchpilot from many synapses. Hence, activated ERK negatively regulates synapse formation, resulting in either the absence of active zones or the formation of active zones without their proper complement of proteins. The Unc-51-dependent inhibition of ERK activity provides a potential mechanism for synapse-specific control of active zone protein composition and release probability.