Trinuclear Calcium Site in the C2 Domain of PKCα/γ Is Prone to Lithium Attack.
Trinuclear Calcium Site in the C2 Domain of PKCα/γ Is Prone to Lithium Attack.
复制标题
PKCα/γ C2结构域的三核钙位点易受锂离子攻击
DOI：
10.1021/acsomega.1c02882
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发表时间：
2021-08-10
期刊：
影响因子：
4.1
通讯作者：
Lim C
中科院分区：
文献类型：
--
作者：
Grauffel C;Weng WH;Dudev T;Lim C
锂（Li+）是双相情感障碍的一线治疗药物，也是肌萎缩侧索硬化症、多发性硬化症和中风等多种疾病的候选药物。尽管是许多研究的迷人主题，但锂的治疗作用机制仍不清楚。迄今为止，已经表明Li+与Mg 2+和Na+竞争，分别使肌醇和神经递质相关信号蛋白的活性正常化。此外，Li+可以与Mg 2+负载的腺苷或三磷酸鸟苷共结合，以改变复合物对水解的敏感性并介导细胞信号传导。双相情感障碍患者表现出异常高的胞质Ca 2+水平和蛋白激酶C（PKC）活性亢进，可通过长期Li+治疗下调。然而，单价Li+可以取代体积较大的二价Ca 2+并抑制PKC活性的可能性尚未被考虑。在这里，使用密度泛函理论计算结合连续介质方法，我们表明，Li+可以取代天然双阳离子从带正电荷的三核网站在C2域的胞质PKCα/γ。这将影响胞浆PKCα/γ的膜对接能力，并降低异常高的膜相关活性PKCα/γ水平，从而下调双相情感障碍患者中发现的PKC过度活性。
Lithium (Li+) is the first-line therapy for bipolar disorder and a candidate drug for various diseases such as amyotrophic lateral sclerosis, multiple sclerosis, and stroke. Despite being the captivating subject of many studies, the mechanism of lithium’s therapeutic action remains unclear. To date, it has been shown that Li+ competes with Mg2+ and Na+ to normalize the activity of inositol and neurotransmitter-related signaling proteins, respectively. Furthermore, Li+ may co-bind with Mg2+-loaded adenosine or guanosine triphosphate to alter the complex’s susceptibility to hydrolysis and mediate cellular signaling. Bipolar disorder patients exhibit abnormally high cytosolic Ca2+ levels and protein kinase C (PKC) hyperactivity that can be downregulated by long-term Li+ treatment. However, the possibility that monovalent Li+ could displace the bulkier divalent Ca2+ and inhibit PKC activity has not been considered. Here, using density functional theory calculations combined with continuum dielectric methods, we show that Li+ may displace the native dication from the positively charged trinuclear site in the C2 domain of cytosolic PKCα/γ. This would affect the membrane-docking ability of cytosolic PKCα/γ and reduce the abnormally high membrane-associated active PKCα/γ levels, thus downregulating the PKC hyperactivity found in bipolar patients.
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影响因子：
15
作者：
Dudev, Todor;Lim, Carmay
通讯作者：
Lim, Carmay
影响因子：
10.6
作者：
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SINGH, H
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作者：
Abrial, Erika;Lucas, Guillaume;Lambas-Senas, Laura
通讯作者：
Lambas-Senas, Laura
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作者：
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King GL
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通讯作者：
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