Samuel Lunenfeld Research Institute, Mount Sinai Hospital Toronto, ON, Canada.
Front Mol Neurosci. 2011 Nov 16;4:40. doi: 10.3389/fnmol.2011.00040. eCollection 2011.
Glycogen synthase kinase-3 (GSK-3) is a widely expressed and highly conserved serine/threonine protein kinase encoded in mammals by two genes that generate two related proteins: GSK-3α and GSK-3β. GSK-3 is active in cells under resting conditions and is primarily regulated through inhibition or diversion of its activity. While GSK-3 is one of the few protein kinases that can be inactivated by phosphorylation, the mechanisms of GSK-3 regulation are more varied and not fully understood. Precise control appears to be achieved by a combination of phosphorylation, localization, and sequestration by a number of GSK-3-binding proteins. GSK-3 lies downstream of several major signaling pathways including the phosphatidylinositol 3' kinase pathway, the Wnt pathway, Hedgehog signaling and Notch. Specific pools of GSK-3, which differ in intracellular localization, binding partner affinity, and relative amount are differentially sensitized to several distinct signaling pathways and these sequestration mechanisms contribute to pathway insulation and signal specificity. Dysregulation of signaling pathways involving GSK-3 is associated with the pathogenesis of numerous neurological and psychiatric disorders and there are data suggesting GSK-3 isoform-selective roles in several of these. Here, we review the current knowledge of GSK-3 regulation and targets and discuss the various animal models that have been employed to dissect the functions of GSK-3 in brain development and function through the use of conventional or conditional knockout mice as well as transgenic mice. These studies have revealed fundamental roles for these protein kinases in memory, behavior, and neuronal fate determination and provide insights into possible therapeutic interventions.
糖原合酶激酶-3（GSK-3）是一种广泛表达且高度保守的丝氨酸/苏氨酸蛋白激酶，在哺乳动物中由两个基因编码，这两个基因产生两种相关的蛋白质：GSK-3α 和 GSK-3β。GSK-3 在静息状态下的细胞中处于活跃状态，主要通过抑制或改变其活性来调节。虽然 GSK-3 是少数几种可通过磷酸化失活的蛋白激酶之一，但 GSK-3 的调节机制更为多样，尚未完全了解。精确的控制似乎是通过磷酸化、定位和与许多 GSK-3 结合蛋白的隔离相结合来实现的。GSK-3 位于几个主要信号通路的下游，包括磷脂酰肌醇 3'激酶通路、Wnt 通路、Hedgehog 信号通路和 Notch。在细胞内定位、结合伙伴亲和力和相对含量上存在差异的特定 GSK-3 池对几种不同的信号通路具有不同的敏感性，这些隔离机制有助于通路隔离和信号特异性。涉及 GSK-3 的信号通路的失调与许多神经和精神疾病的发病机制有关，并且有数据表明 GSK-3 同工型在其中几种疾病中具有选择性作用。在这里，我们综述了 GSK-3 调节和靶标的最新知识，并讨论了各种动物模型，这些模型通过使用传统或条件性敲除小鼠以及转基因小鼠，用于剖析 GSK-3 在大脑发育和功能中的作用。这些研究揭示了这些蛋白激酶在记忆、行为和神经元命运决定中的基本作用，并为可能的治疗干预提供了思路。
