Fragile X mental retardation protein controls synaptic vesicle exocytosis by modulating N-type calcium channel density.
Fragile X mental retardation protein controls synaptic vesicle exocytosis by modulating N-type calcium channel density.
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DOI：
10.1038/ncomms4628
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发表时间：
2014-04-07
影响因子：
16.6
通讯作者：
Dolphin, Annette C.
中科院分区：
文献类型：
--
作者：
Ferron, Laurent;Nieto-Rostro, Manuela;Cassidy, John S.;Dolphin, Annette C.
脆性X综合征(FXS)是最常见的遗传性智力低下形式，以突触功能障碍为特征。突触传递在很大程度上依赖于突触前钙离子通过电压门控钙通道(Cav)进入。在这里，我们发现神经元N型Cav通道(Cav2.2)的功能表达受脆性X智力低下蛋白(FMRP)的调节。我们发现，在背根神经节神经元中，FMRP基因敲除增加了胞体和突触前终末的Cav通道密度。然后，我们证明了FMRP通过靶向蛋白酶体降解的通道来控制Cav2.2的表面表达。FMRP和Cav2.2之间的相互作用发生在FMRP的羧基末端结构域和Cav2.2的已知与神经递质释放机制相互作用的结构域之间。最后，我们发现FMRP通过Cav2.2通道控制突触的胞吐。我们的数据表明，FMRP是突触前活动的有效调节因子，它的丢失可能导致FXS的突触功能障碍。脆性X智力低下蛋白的突变与脆性X综合征的突触功能障碍有关。这里，Ferron等人。表明脆性X智力低下蛋白通过调节突触前终末N型钙通道的密度来维持正常的神经传递。
Fragile X syndrome (FXS), the most common heritable form of mental retardation, is characterized by synaptic dysfunction. Synaptic transmission depends critically on presynaptic calcium entry via voltage-gated calcium (CaV) channels. Here we show that the functional expression of neuronal N-type CaV channels (CaV2.2) is regulated by fragile X mental retardation protein (FMRP). We find that FMRP knockdown in dorsal root ganglion neurons increases CaV channel density in somata and in presynaptic terminals. We then show that FMRP controls CaV2.2 surface expression by targeting the channels to the proteasome for degradation. The interaction between FMRP and CaV2.2 occurs between the carboxy-terminal domain of FMRP and domains of CaV2.2 known to interact with the neurotransmitter release machinery. Finally, we show that FMRP controls synaptic exocytosis via CaV2.2 channels. Our data indicate that FMRP is a potent regulator of presynaptic activity, and its loss is likely to contribute to synaptic dysfunction in FXS. Mutations in the fragile X mental retardation protein are implicated in synaptic dysfunction in fragile X syndrome. Here, Ferron et al. show that fragile X mental retardation protein maintains proper neurotransmission by regulating the density of N-type calcium channels in the presynaptic terminal.
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影响因子：
16.2
作者：
Edbauer, Dieter;Neilson, Joel R.;Foster, Kelly A.;Wang, Chi-Fong;Seeburg, Daniel P.;Batterton, Matthew N.;Tada, Tomoko;Dolan, Bridget M.;Sharp, Phillip A.;Sheng, Morgan
通讯作者：
Sheng, Morgan
影响因子：
5.3
作者：
Hu, H;Shao, LR;Storm, JF
通讯作者：
Storm, JF
影响因子：
25
作者：
Altier, C;Khosravani, H;Zamponi, GW
通讯作者：
Zamponi, GW
影响因子：
16.2
作者：
Deng PY;Rotman Z;Blundon JA;Cho Y;Cui J;Cavalli V;Zakharenko SS;Klyachko VA
通讯作者：
Klyachko VA
影响因子：
25
作者：
Altier, Christophe;Garcia-Caballero, Agustin;Zamponi, Gerald W.
通讯作者：
Zamponi, Gerald W.