Regulators of G protein signaling and transient activation of signaling - Experimental and computational analysis reveals negative and positive feedback controls on G protein activity
Regulators of G protein signaling and transient activation of signaling - Experimental and computational analysis reveals negative and positive feedback controls on G protein activity
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DOI：
10.1074/jbc.m308432200
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发表时间：
2003-11-21
影响因子：
4.8
通讯作者：
Dohlman, HG
中科院分区：
文献类型：
--
作者：
Hao, N;Yildirim, N;Dohlman, HG
细胞对激素和神经递质的反应必然是短暂的。酵母中的交配信息素信号是典型的。信号起始需要细胞表面受体、G蛋白异源三聚体和下游效应物。信号失活需要Sst 2，这是一种G蛋白信号传导（RGS）蛋白的调节剂，可加速GT3活性。我们对RGS和G蛋白表达进行了定量分析，并设计了描述其体内活性的计算模型。这些结果表明RGS蛋白的信息素依赖性转录诱导构成了导致脱敏的负反馈环。建模还表明存在导致通路再敏感化的正反馈回路。在证实该模型，我们发现，RGS蛋白是泛素化和降解的信息素刺激。我们确定和定量这些正反馈和负反馈回路，这占在体内观察到的外部信号的瞬态响应。
Cellular responses to hormones and neurotransmitters are necessarily transient. The mating pheromone signal in yeast is typical. Signal initiation requires cell surface receptors, a G protein heterotrimer, and downstream effectors. Signal inactivation requires Sst2, a regulator of G protein signaling ( RGS) protein that accelerates GTPase activity. We conducted a quantitative analysis of RGS and G protein expression and devised computational models that describe their activity in vivo. These results indicated that pheromone- dependent transcriptional induction of the RGS protein constitutes a negative feedback loop that leads to desensitization. Modeling also suggested the presence of a positive feedback loop leading to resensitization of the pathway. In confirmation of the model, we found that the RGS protein is ubiquitinated and degraded in response to pheromone stimulation. We identified and quantitated these positive and negative feedback loops, which account for the transient response to external signals observed in vivo.