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首页> 外文期刊>The Journal of Neuroscience: The Official Journal of the Society for Neuroscience >Cell-specific fine-tuning of neuronal excitability by differential expression of modulator protein isoforms
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Cell-specific fine-tuning of neuronal excitability by differential expression of modulator protein isoforms

机译：通过调节蛋白同工型的差异表达对神经元兴奋性进行细胞特异性微调

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摘要

SLOB (SLOWPOKE-binding protein) modulates the Drosophila SLOWPOKE calcium-activated potassium channel. We have shown previously that SLOB deletion or RNAi knockdown decreases excitability of neurosecretory pars intercerebralis (PI) neurons in the adult Drosophila brain. In contrast, we found that SLOB deletion/knockdown enhances neurotransmitter release from motor neurons at the fly larval neuromuscular junction, suggesting an increase in excitability. Because two prominent SLOB isoforms, SLOB57 and SLOB71, modulate SLOWPOKE channels in opposite directions in vitro, we investigated whether divergent expression patterns of these two isoforms might underlie the differential modulation of excitability in PI and motor neurons. By performing detailed in vitro and in vivo analysis, we found strikingly different modes of regulatory control by the slob57 and slob71 promoters. The slob71, but not slob57, promoter contains binding sites for the Hunchback and Mirror transcriptional repressors. Furthermore, several core promoter elements that are absent in the slob57 promoter coordinately drive robust expression of a luciferase vector by the slob71 promoter in vitro. In addition, we visualized the expression patterns of the slob57 and slob71 promoters in vivo and found clear spatiotemporal differences in promoter activity. SLOB57 is expressed prominently in adult PI neurons, whereas larval motor neurons exclusively express SLOB71. In contrast, at the larval neuromuscular junction, SLOB57 expression appears to be restricted mainly to a subset of glial cells. Our results illustrate how the use of alternative transcriptional start sites within an ion channel modulator locus coupled with functionally relevant alternative splicing can be used to fine-tune neuronal excitability in a cell-specific manner.
机译：SLOB（SLOWPOKE结合蛋白）调节果蝇SLOWPOKE钙激活的钾通道。以前我们已经表明，SLOB缺失或RNAi敲低会降低成人果蝇大脑中神经分泌性脑间神经（PI）神经元的兴奋性。相反，我们发现SLOB缺失/敲低增强了蝇幼虫神经肌肉接头处运动神经元的神经递质释放，提示兴奋性增加。因为两个突出的SLOB亚型SLOB57和SLOB71在体外以相反的方向调节SLOWPOKE通道，所以我们研究了这两种亚型的不同表达模式是否可能是PI和运动神经元兴奋性差异调节的基础。通过进行详细的体外和体内分析，我们发现slob57和slob71启动子的调控方式非常不同。 slob71（而非slob57）启动子包含Hunchback和Mirror转录阻遏物的结合位点。此外，slob57启动子中不存在的几个核心启动子元件通过slob71启动子在体外协调驱动萤光素酶载体的稳定表达。此外，我们可视化了slob57和slob71启动子的体内表达模式，发现启动子活性存在明显的时空差异。 SLOB57在成年PI神经元中显着表达，而幼虫运动神经元专门表达SLOB71。相反，在幼虫神经肌肉接头处，SLOB57表达似乎主要限于神经胶质细胞的一部分。我们的结果说明了如何使用离子通道调节基因座中的替代转录起始位点以及功能相关的替代剪接，可以以细胞特异性方式微调神经元兴奋性。

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