Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
School of Medicine, Chang Gung University; Community Medicine Research Center & Department of Psychiatry, Chang Gung Memorial Hospital, Keelung, Taiwan.
Sci Rep. 2019 Jul 16;9(1):10255. doi: 10.1038/s41598-019-46655-1.
Potassium channel tetramerization domain containing 12 (KCTD12), the auxiliary GABA receptor subunit, is identified as a susceptibility gene for bipolar I (BPI) disorder in the Han Chinese population. Moreover, the single-nucleotide polymorphism (SNP) rs17026688 in glutamate decarboxylase-like protein 1 (GADL1) is shown to be associated with lithium response in Han Chinese BPI patients. In this study, we demonstrated for the first time the relationship among lithium, GADL1, and KCTD12. In circulating CD11b macrophage cells, BPI patients showed a significantly higher percentage of KCTD12 expression than healthy controls. Among BPI patients, carriers of the 'T' allele (i.e., CT or TT) at site rs17026688 were found to secrete lower amounts of GADL1 but higher amounts of GABA b receptor 2 (GABBR2) in the plasma. In human SH-SY5Y neuroblastoma cells, lithium treatment increased the percentage of KCTD12 expression. Through inhibition of glycogen synthase kinase-3 (GSK-3), lithium induced cyclic AMP-response element binding protein (CREB)-mediated KCTD12 promoter activation. On the other hand, GADL1 overexpression enhanced GSK-3 activation and inhibited KCTD12 expression. We found that lithium induced, whereas GADL1 inhibited, KCTD12 expression. These findings suggested that KCTD12 may be an important gene with respect to neuron excitability and lithium response in BPI patients. Therefore, targeting GSK-3 activity and/or KCTD12 expression may constitute a possible therapeutic strategy for treating patients with BPI disorder.
钾通道四聚化结构域包含 12 个蛋白（KCTD12），作为 GABA 受体辅助亚基，被鉴定为汉族人群中双相 I 型（BPI）障碍的易感基因。此外，谷氨酸脱羧酶样蛋白 1（GADL1）中的单核苷酸多态性（SNP）rs17026688 与汉族 BPI 患者的锂反应相关。在这项研究中，我们首次证明了锂、GADL1 和 KCTD12 之间的关系。在循环 CD11b 巨噬细胞中，BPI 患者的 KCTD12 表达比例明显高于健康对照组。在 BPI 患者中，位于 rs17026688 位点的 'T' 等位基因（即 CT 或 TT）携带者在血浆中分泌的 GADL1 较少，但 GABA b 受体 2（GABBR2）较多。在人 SH-SY5Y 神经母细胞瘤细胞中，锂处理增加了 KCTD12 表达的比例。通过抑制糖原合酶激酶-3（GSK-3），锂诱导环腺苷酸反应元件结合蛋白（CREB）介导的 KCTD12 启动子激活。另一方面，GADL1 过表达增强了 GSK-3 的激活并抑制了 KCTD12 的表达。我们发现，锂诱导而 GADL1 抑制 KCTD12 的表达。这些发现表明 KCTD12 可能是 BPI 患者神经元兴奋性和锂反应的重要基因。因此，靶向 GSK-3 活性和/或 KCTD12 表达可能是治疗 BPI 障碍患者的一种潜在治疗策略。
