Diacylglycerol kinase (DGKA) regulates the effect of the epilepsy and bipolar disorder treatment valproic acid in Dictyostelium discoideum.
Diacylglycerol kinase (DGKA) regulates the effect of the epilepsy and bipolar disorder treatment valproic acid in Dictyostelium discoideum.
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DOI：
10.1242/dmm.035600
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发表时间：
2018-08-21
影响因子：
4.3
通讯作者：
Williams RSB
中科院分区：
文献类型：
--
作者：
Kelly E;Sharma D;Wilkinson CJ;Williams RSB
丙戊酸（VPA）是治疗癫痫和双相情感障碍的常用药物；然而，与这两种疾病有关的共同细胞机制尚未提出。在这里，我们探讨了二酰基甘油激酶（DGK）在调节VPA治疗这两种疾病的作用中发挥作用的可能性，使用生物医学模型盘状盘齿龙。DGK酶提供磷酸肌苷循环途径的第一步，涉及癫痫活动。它们还调节二酰基甘油（DAG）的水平，从而调节与双相情感障碍相关信号传导相关的蛋白激酶C （PKC）的活性。在这里，我们表明单个盘基骨菌dgkA基因的消融导致对VPA对细胞行为的急性影响的敏感性降低。dgkA的丧失也降低了在发育期间长时间暴露于VPA的敏感性。为了区分这种dgkA依赖机制在癫痫和双相情感障碍治疗中的潜在作用，我们进一步表明dgkA零突变体对一系列具有癫痫控制活性的结构不同的支链中链脂肪酸的发育影响和双相情感障碍治疗锂具有抗性。最后，我们发现VPA、锂和新型癫痫治疗通过DAG调节起作用，DGKA的存在是治疗后化合物特异性DAG水平升高的必要条件。因此，这些实验表明，在Dictyostelium中，DGKA的丧失减弱了与癫痫和双相情感障碍治疗相关的VPA的常见细胞效应，并且应该研究一系列具有这种效应的新化合物作为替代治疗药物。本文以第一人称采访了该论文的第一作者。编者按：在这里，我们使用一个易于处理的模型系统，Dictyostelium disideum，我们表明二酰基甘油激酶活性可能有助于癫痫和双相情感障碍治疗的细胞机制，丙戊酸。
Valproic acid (VPA) provides a common treatment for both epilepsy and bipolar disorder; however, common cellular mechanisms relating to both disorders have yet to be proposed. Here, we explore the possibility of a diacylglycerol kinase (DGK) playing a role in regulating the effect of VPA relating to the treatment of both disorders, using the biomedical model Dictyostelium discoideum. DGK enzymes provide the first step in the phosphoinositide recycling pathway, implicated in seizure activity. They also regulate levels of diacylglycerol (DAG), thereby regulating the protein kinase C (PKC) activity that is linked to bipolar disorder-related signalling. Here, we show that ablation of the single Dictyostelium dgkA gene results in reduced sensitivity to the acute effects of VPA on cell behaviour. Loss of dgkA also provides reduced sensitivity to VPA in extended exposure during development. To differentiate a potential role for this DGKA-dependent mechanism in epilepsy and bipolar disorder treatment, we further show that the dgkA null mutant is resistant to the developmental effects of a range of structurally distinct branched medium-chain fatty acids with seizure control activity and to the bipolar disorder treatment lithium. Finally, we show that VPA, lithium and novel epilepsy treatments function through DAG regulation, and the presence of DGKA is necessary for compound-specific increases in DAG levels following treatment. Thus, these experiments suggest that, in Dictyostelium, loss of DGKA attenuates a common cellular effect of VPA relating to both epilepsy and bipolar disorder treatments, and that a range of new compounds with this effect should be investigated as alternative therapeutic agents. This article has an associated First Person interview with the first author of the paper. Editor's choice: Here, using a tractable model system, Dictyostelium discoideum, we show that diacylglycerol kinase activity might contribute to the cellular mechanism of action of the epilepsy and bipolar disorder treatment, valproic acid.
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DOI：
10.1124/jpet.114.218768
发表时间：
2015-01-01
影响因子：
3.5
作者：
Chang, Pishan;Zuckermann, Alexandra M. E.;Williams, Robin S. B.
通讯作者：
Williams, Robin S. B.
影响因子：
10.6
作者：
FRIEDMAN, E;WANG, HY;SINGH, H
通讯作者：
SINGH, H
影响因子：
11
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Baum, A. E.;Akula, N.;McMahon, F. J.
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影响因子：
4.8
作者：
AbuElneel, K;Karchi, M;Ravid, S
通讯作者：
Ravid, S
影响因子：
4.8
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Fakas, Stylianos;Konstantinou, Chrysanthos;Carman, George M.
通讯作者：
Carman, George M.