Glycogen Synthase Kinase 3: Ion Channels, Plasticity, and Diseases.
Glycogen Synthase Kinase 3: Ion Channels, Plasticity, and Diseases.
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DOI：
10.3390/ijms23084413
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发表时间：
2022-04-16
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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作者：
糖原合成酶激酶3β（Glycogen synthase kinase 3β，GSK 3）是一种多功能的丝氨酸/苏氨酸（serine/threonine，S/T）激酶，在所有真核细胞中均有表达。GSK 3 β在中枢神经系统的神经元中高度富集，在中枢神经系统中，GSK 3 β作为神经元功能关键受体下游细胞内信号传导的中枢枢纽。与其他激酶不同，GSK 3 β具有组成性活性，其调节主要涉及通过上游调节途径的抑制，而不是增加活化。通过复杂的会聚信号系统，活性和非活性GSK 3 β的微调平衡充当许多引发和未引发底物磷酸化的中心点。尽管目前还不清楚GSK 3 β的全部分子靶点，但最近的研究结果表明电压门控离子通道是GSK 3 β的下游靶点。在这里，我们讨论了GSK 3 β磷酸化电压门控Na+通道（Nav1.2和Nav1.6）和电压门控K+通道（Kv 4和Kv 7）的直接和间接机制，以及它们对内在兴奋性、神经元可塑性和行为的生理作用。我们还提供了证据证明不平衡的GSK 3 β活性如何导致适应不良的可塑性，最终使神经元回路更脆弱，增加了发展神经精神疾病的风险。总之，电压门控离子通道的GSK 3 β依赖性调节可作为神经治疗开发的重要药理学靶点。
Glycogen synthase kinase 3β (GSK3) is a multifaceted serine/threonine (S/T) kinase expressed in all eukaryotic cells. GSK3β is highly enriched in neurons in the central nervous system where it acts as a central hub for intracellular signaling downstream of receptors critical for neuronal function. Unlike other kinases, GSK3β is constitutively active, and its modulation mainly involves inhibition via upstream regulatory pathways rather than increased activation. Through an intricate converging signaling system, a fine-tuned balance of active and inactive GSK3β acts as a central point for the phosphorylation of numerous primed and unprimed substrates. Although the full range of molecular targets is still unknown, recent results show that voltage-gated ion channels are among the downstream targets of GSK3β. Here, we discuss the direct and indirect mechanisms by which GSK3β phosphorylates voltage-gated Na+ channels (Nav1.2 and Nav1.6) and voltage-gated K+ channels (Kv4 and Kv7) and their physiological effects on intrinsic excitability, neuronal plasticity, and behavior. We also present evidence for how unbalanced GSK3β activity can lead to maladaptive plasticity that ultimately renders neuronal circuitry more vulnerable, increasing the risk for developing neuropsychiatric disorders. In conclusion, GSK3β-dependent modulation of voltage-gated ion channels may serve as an important pharmacological target for neurotherapeutic development.
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DOI：
10.1083/jcb.200805169
发表时间：
2008-12-15
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bréchet A;Fache MP;Brachet A;Ferracci G;Baude A;Irondelle M;Pereira S;Leterrier C;Dargent B
通讯作者：
Dargent B
影响因子：
4.8
作者：
Bradley CA;Peineau S;Taghibiglou C;Nicolas CS;Whitcomb DJ;Bortolotto ZA;Kaang BK;Cho K;Wang YT;Collingridge GL
通讯作者：
Collingridge GL
影响因子：
4.8
作者：
Di Re J;Hsu WJ;Kayasandik CB;Fularczyk N;James TF;Nenov MN;Negi P;Marosi M;Scala F;Prasad S;Labate D;Laezza F
通讯作者：
Laezza F
影响因子：
3.7
作者：
Akin EJ;Solé L;Dib-Hajj SD;Waxman SG;Tamkun MM
通讯作者：
Tamkun MM
影响因子：
4.4
作者：
Berendt, Frank J.;Park, Kang-Sik;Trimmer, James S.
通讯作者：
Trimmer, James S.