New Insights in Glucocorticoid Receptor Signaling-More Than Just a Ligand-Binding Receptor.
New Insights in Glucocorticoid Receptor Signaling-More Than Just a Ligand-Binding Receptor.
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DOI：
10.3389/fendo.2017.00016
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发表时间：
2017
影响因子：
5.2
通讯作者：
Assreuy J
中科院分区：
文献类型：
--
作者：
Scheschowitsch K;Leite JA;Assreuy J
经典糖皮质激素（GC）的临床应用因其引起的许多副作用和在某些疾病中观察到的对GC的耐药性而受到限制。由于绝大多数GC效应依赖于糖皮质激素受体（GR）的激活，许多研究小组都致力于更好地了解涉及这些受体的信号通路。转基因动物模型和受体的遗传修饰为GR的作用机制带来了巨大的洞察力。这反过来又为寻找选择性GR调节剂打开了一个新的窗口，理想情况下，这些调节剂可能具有激动和拮抗联合作用，并激活一个特定的信号通路，诱导主要的转抑制或转激活机制。另一个重要的研究领域涉及影响GR的翻译后修饰，从而影响其信号传导和功能。在这篇小综述中，我们讨论了GR信号的许多方面，以及GR的非配体激活等发现，这些发现增加了GR信号通路的另一层复杂性。虽然最近有一些数据被添加到GR领域，但还有很多工作要做，特别是要找出这些替代GR信号通路的生物学相关性。提高对替代GR信号通路的认识，了解这些通路如何相互通信以及在哪些情况下它们是相关的，可能有助于开发新的策略来利用它，并提高GC或其他化合物的功效，使副作用降到最低。
The clinical use of classical glucocorticoids (GC) is narrowed by the many side effects it causes and the resistance to GC observed in some diseases. Since the great majority of GC effects depend on the activation of a glucocorticoid receptor (GR), many research groups had focused to better understand the signaling pathways involving those receptors. Transgenic animal models and genetic modifications of the receptor brought a huge insight into GR mechanisms of action. This in turn opened a new window for the search of selective GR modulators that ideally may have agonistic and antagonistic combined effects and activate one specific signaling pathway, inducing mostly transrepression or transactivation mechanisms. Another important research field concerns to posttranslational modifications that affect the GR and consequently also affect its signaling and function. In this mini review, we discuss many of those aspects of GR signaling, as well as findings like the ligand-independent activation of GR, which add another layer of complexity in GR signaling pathways. Although several recent data have been added to the GR field, much work has yet to be done, especially to find out the biological relevance of those alternative GR signaling pathways. Improving the knowledge about alternative GR signaling pathways and understanding how these pathways intercommunicate and in which situations they are relevant might help to develop new strategies to take benefit of it and to improve GC or other compounds efficacy causing minimal side effects.