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FMRP regulates presynaptic localization of neuronal voltage gated calcium channels.
Neurobiology of Disease ( IF 5.1 ) Pub Date : 2020-01-25 , DOI: 10.1016/j.nbd.2020.104779
Laurent Ferron 1 , Cesare G Novazzi 1 , Kjara S Pilch 1 , Cristian Moreno 1 , Krishma Ramgoolam 1 , Annette C Dolphin 1
Affiliation  

Fragile X syndrome (FXS), the most common form of inherited intellectual disability and autism, results from the loss of fragile X mental retardation protein (FMRP). We have recently identified a direct interaction of FMRP with voltage-gated Ca2+ channels that modulates neurotransmitter release. In the present study we used a combination of optophysiological tools to investigate the impact of FMRP on the targeting of voltage-gated Ca2+ channels to the active zones in neuronal presynaptic terminals. We monitored Ca2+ transients at synaptic boutons of dorsal root ganglion (DRG) neurons using the genetically-encoded Ca2+ indicator GCaMP6f tagged to synaptophysin. We show that knock-down of FMRP induces an increase of the amplitude of the Ca2+ transient in functionally-releasing presynaptic terminals, and that this effect is due to an increase of N-type Ca2+ channel contribution to the total Ca2+ transient. Dynamic regulation of CaV2.2 channel trafficking is key to the function of these channels in neurons. Using a CaV2.2 construct with an α-bungarotoxin binding site tag, we further investigate the impact of FMRP on the trafficking of CaV2.2 channels. We show that forward trafficking of CaV2.2 channels from the endoplasmic reticulum to the plasma membrane is reduced when co-expressed with FMRP. Altogether our data reveal a critical role of FMRP on localization of CaV channels to the presynaptic terminals and how its defect in a context of FXS can profoundly affect synaptic transmission.

中文翻译:

FMRP 调节神经元电压门控钙通道的突触前定位。

脆性 X 综合征 (FXS) 是遗传性智力障碍和自闭症的最常见形式,是由脆性 X 智力迟钝蛋白 (FMRP) 缺失引起的。我们最近确定了 FMRP 与调节神经递质释放的电压门控 Ca2+ 通道的直接相互作用。在本研究中,我们结合使用光生理学工具来研究 FMRP 对电压门控 Ca2+ 通道靶向神经元突触前末梢活性区的影响。我们使用标记为突触素的基因编码的 Ca2+ 指示剂 GCaMP6f 监测背根神经节 (DRG) 神经元突触处的 Ca2+ 瞬变。我们表明,FMRP 的敲除会导致功能释放突触前末端中 Ca2+ 瞬变的幅度增加,并且这种效应是由于 N 型 Ca2+ 通道对总 Ca2+ 瞬态的贡献增加。CaV2.2 通道运输的动态调节是神经元中这些通道功能的关键。使用带有 α-银环蛇毒素结合位点标签的 CaV2.2 构建体,我们进一步研究了 FMRP 对 CaV2.2 通道运输的影响。我们表明,当与 FMRP 共表达时,CaV2.2 通道从内质网到质膜的前向运输减少。总之,我们的数据揭示了 FMRP 在 CaV 通道定位到突触前末端的关键作用,以及它在 FXS 环境中的缺陷如何深刻影响突触传递。使用带有 α-银环蛇毒素结合位点标签的 CaV2.2 构建体,我们进一步研究了 FMRP 对 CaV2.2 通道运输的影响。我们表明,当与 FMRP 共表达时,CaV2.2 通道从内质网到质膜的前向运输减少。总而言之,我们的数据揭示了 FMRP 在 CaV 通道定位到突触前末端的关键作用,以及它在 FXS 环境中的缺陷如何深刻影响突触传递。使用带有 α-银环蛇毒素结合位点标签的 CaV2.2 构建体,我们进一步研究了 FMRP 对 CaV2.2 通道运输的影响。我们表明,当与 FMRP 共表达时,CaV2.2 通道从内质网到质膜的前向运输减少。总之,我们的数据揭示了 FMRP 在 CaV 通道定位到突触前末端的关键作用,以及它在 FXS 环境中的缺陷如何深刻影响突触传递。
更新日期:2020-01-26
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