Information Transfer in Gonadotropin-releasing Hormone (GnRH) Signaling: EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK)-MEDIATED FEEDBACK LOOPS CONTROL HORMONE SENSING.
Information Transfer in Gonadotropin-releasing Hormone (GnRH) Signaling: EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK)-MEDIATED FEEDBACK LOOPS CONTROL HORMONE SENSING.
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DOI：
10.1074/jbc.m115.686964
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发表时间：
2016-01-29
期刊：
影响因子：
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通讯作者：
McArdle CA
中科院分区：
文献类型：
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作者：
Garner KL;Perrett RM;Voliotis M;Bowsher C;Pope GR;Pham T;Caunt CJ;Tsaneva-Atanasova K;McArdle CA
细胞信号通路是嘈杂的通信通道，从信息论导出的统计测量可以用来量化它们传递的信息。在这里，我们使用单细胞信号传导措施来计算作为信息传递的措施，通过促性腺激素释放激素（GnRH）受体（GnRHR）的细胞外信号调节激酶（ERK）或活化的T细胞的核因子（NFAT）的互信息。这表明互信息值<1位，这意味着单个GnRH反应细胞甚至不能明确区分两个同等可能的输入浓度。解决可能的机制，减轻信息丢失，我们专注于ERK通路，并开发了一个随机激活模型，将负反馈和组成性活动。模型模拟揭示了快速（分钟）和慢速（分钟-小时）负反馈回路之间的相互作用，在中间反馈水平的最大信息传递。与此一致，实验表明，减少负反馈（通过表达无催化活性的ERK 2）和增加负反馈（通过Egr 1驱动的双特异性磷酸酶5（DUSP 5）的表达）都减少了从GnRHR到ERK的信息传递。通过阻断蛋白质合成（以防止GnRH增加DUSP表达）也可以降低DUSP，但对于不同的GnRH受体（进行或不进行快速同源脱敏）没有差异。因此，通过这些受体的信息传递的第一个统计措施表明，单个细胞是不可靠的GnRH浓度的传感器，这种可靠性是最大的在中间水平的ERK介导的负反馈，但不受受体脱敏。
Cell signaling pathways are noisy communication channels, and statistical measures derived from information theory can be used to quantify the information they transfer. Here we use single cell signaling measures to calculate mutual information as a measure of information transfer via gonadotropin-releasing hormone (GnRH) receptors (GnRHR) to extracellular signal-regulated kinase (ERK) or nuclear factor of activated T-cells (NFAT). This revealed mutual information values <1 bit, implying that individual GnRH-responsive cells cannot unambiguously differentiate even two equally probable input concentrations. Addressing possible mechanisms for mitigation of information loss, we focused on the ERK pathway and developed a stochastic activation model incorporating negative feedback and constitutive activity. Model simulations revealed interplay between fast (min) and slow (min-h) negative feedback loops with maximal information transfer at intermediate feedback levels. Consistent with this, experiments revealed that reducing negative feedback (by expressing catalytically inactive ERK2) and increasing negative feedback (by Egr1-driven expression of dual-specificity phosphatase 5 (DUSP5)) both reduced information transfer from GnRHR to ERK. It was also reduced by blocking protein synthesis (to prevent GnRH from increasing DUSP expression) but did not differ for different GnRHRs that do or do not undergo rapid homologous desensitization. Thus, the first statistical measures of information transfer via these receptors reveals that individual cells are unreliable sensors of GnRH concentration and that this reliability is maximal at intermediate levels of ERK-mediated negative feedback but is not influenced by receptor desensitization.