Minireview: Targeting GPCR Activated ERK Pathways for Drug Discovery.
Minireview: Targeting GPCR Activated ERK Pathways for Drug Discovery.
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Minireview：靶向GPCR激活的ERK途径进行药物发现。
DOI：
10.2174/2213988501307010009
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Kongsamut S
中科院分区：
文献类型：
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作者：
Eishingdrelo H;Kongsamut S
近年来已经清楚的是，在GPCR激活时采用多种信号转导途径。由GPCR激活的主要细胞效应物之一是细胞外信号调节激酶（ERK）。G蛋白和β-arrestin介导的信号通路均可导致ERK激活。然而，根据活化途径，活化的ERK 1/2的亚细胞目的地可能不同。G蛋白依赖性ERK激活导致活性ERK易位至细胞核，而通过抑制蛋白依赖性机制激活的ERK大部分保留在细胞质中。活化的ERK 1/2的亚细胞位置决定下游信号级联。ERK 1/2的许多底物存在于细胞核中：参与基因转录、细胞增殖和分化的核转录因子。ERK 1/2底物也存在于细胞质和其他细胞器中：它们可能在翻译、有丝分裂、凋亡和与其他信号通路的串扰中发挥作用。因此，确定GPCR配体介导的活化ERK 1/2的特定亚细胞位置对于将信号传导途径与细胞生理功能相关联将是重要的。虽然GPCR刺激的选择性ERK途径活化已在几种受体系统中进行了研究，但尚未认真研究这些不同的信号级联用于治疗。许多旧的候选药物是从基于G蛋白信号传导测定的筛选中鉴定的，并且它们对β-抑制蛋白信号传导途径的活性大多是未知的，特别是关于它们的亚细胞ERK途径。随着今天对复杂GPCR信号通路的了解，药物发现不再依赖于单通路方法。由于ERK激活是一种重要的信号通路，与多种生理功能相关，因此靶向ERK通路，特别是特异性亚细胞激活通路，将为GPCR药物的发现提供新的途径。
It has become clear in recent years that multiple signal transduction pathways are employed upon GPCR activation. One of the major cellular effectors activated by GPCRs is extracellular signal-regulated kinase (ERK). Both G-protein and β-arrestin mediated signaling pathways can lead to ERK activation. However, depending on activation pathway, the subcellular destination of activated ERK1/2 may be different. G-protein -dependent ERK activation results in the translocation of active ERK to the nucleus, whereas ERK activated via an arrestin-dependent mechanism remains largely in the cytoplasm. The subcellular location of activated ERK1/2 determines the downstream signaling cascade. Many substrates of ERK1/2 are found in the nucleus: nuclear transcription factors that participate in gene transcription, cell proliferation and differentiation. ERK1/2 substrates are also found in cytosol and other cellular organelles: they may play roles in translation, mitosis, apoptosis and cross-talk with other signaling pathways. Therefore, determining specific subcellular locations of activated ERK1/2 mediated by GPCR ligands would be important in correlating signaling pathways with cellular physiological functions. While GPCR-stimulated selective ERK pathway activation has been studied in several receptor systems, exploitation of these different signaling cascades for therapeutics has not yet been seriously pursued. Many old drug candidates were identified from screens based on G-protein signaling assays, and their activity on β-arrestin signaling pathways being mostly unknown, especially regarding their subcellular ERK pathways. With today’s knowledge of complicated GPCR signaling pathways, drug discovery can no longer rely on single-pathway approaches. Since ERK activation is an important signaling pathway and associated with many physiological functions, targeting the ERK pathway, especially specific subcellular activation pathways should provide new avenues for GPCR drug discovery.