Abstract:
Glycogen synthase kinase 3 (GSK-3) is a serine/threonine kinase widely expressed in various tissues and organs. Unlike other kinases, GSK-3 is active under resting conditions and is inactivated upon stimulation. In mammals, GSK-3 includes GSK-3 α and GSK-3β isoforms encoded by two homologous genes, namely, GSK3A and GSK3B. GSK-3β is essential for the control of glucose metabolism, signal transduction, and tissue homeostasis. As more than 100 known proteins have been identified as GSK-3β substrates, it is sometimes referred to as a moonlighting kinase. Previous studies have elucidated the regulation modes of GSK-3β. GSK-3β is involved in almost all aspects of brain functions, such as neuronal morphology, synapse formation, neuroinflammation, and neurological disorders. Recently, several comparatively specific small molecules have facilitated the chemical manipulation of this enzyme within cellular systems, leading to the discovery of novel inhibitors for GSK-3β. Despite these advancements, the therapeutic significance of GSK-3β as a drug target is still complicated by uncertainties surrounding the potential of inhibitors to stimulate tumorigenesis. This review provides a comprehensive overview of the intricate mechanisms of this enzyme and evaluates the existing evidence regarding the therapeutic potential of GSK-3β in brain diseases, including Alzheimer\'s disease, Parkinson\'s disease, mood disorders, and glioblastoma.
摘要:
糖原合成酶激酶3(GSK-3)是一种广泛表达于多种组织和器官中的丝氨酸/苏氨酸激酶。不像其他激酶,GSK-3在静息条件下是活性的,并且在刺激时是失活的。在哺乳动物中,GSK-3包括由两个同源基因编码的GSK-3α和GSK-3β亚型,即,GSK3A和GSK3B。GSK-3β对控制葡萄糖代谢至关重要,信号转导,和组织稳态。由于已有100多种已知蛋白质被鉴定为GSK-3β底物,它有时被称为月光激酶。先前的研究已经阐明了GSK-3β的调节模式。GSK-3β几乎涉及大脑功能的所有方面,如神经元形态,突触形成,神经炎症,和神经系统疾病。最近,几个相对特异的小分子促进了这种酶在细胞系统内的化学操作,导致发现了GSK-3β的新型抑制剂。尽管取得了这些进步,GSK-3β作为药物靶标的治疗意义仍然因抑制剂刺激肿瘤发生的潜在不确定性而复杂化.这篇综述全面概述了这种酶的复杂机制,并评估了有关GSK-3β在脑疾病中的治疗潜力的现有证据。包括老年痴呆症,帕金森病,情绪障碍,和胶质母细胞瘤.