Department of Chemistry, Graduate School of Science, Chiba University, Japan.
FEBS Lett. 2021 May;595(9):1313-1321. doi: 10.1002/1873-3468.14059. Epub 2021 Mar 8.
The molecular mechanisms generating the mania-like abnormal behaviors caused by diacylglycerol (DG) kinase (DGK) η deficiency remain unclear. Here, we found that DGKη knockout markedly increased dopamine (DA) levels in the midbrain (DA-producing region, 2.8-fold) and cerebral cortex (DA projection region, 1.2-fold). Moreover, DGKη deficiency significantly augmented phosphorylated DA transporter (DAT) levels (1.4-fold increase), which induce DA efflux to the synaptic cleft, in the cerebral cortex. Moreover, phosphorylation levels of protein kinase C-β, which is activated by DG and involved in DAT phosphorylation, were also increased. DAT expressed in Neuro-2a cells recruited DGKη to the plasma membrane and colocalized with it. These results strongly suggest that dopaminergic hyperfunction caused by DGKη deficiency in the brain leads to mania-like behaviors.
DG 激酶（DGK）η 缺乏导致的类似躁狂的异常行为的分子机制尚不清楚。在这里，我们发现 DGKη 敲除显著增加了中脑（多巴胺产生区域，增加 2.8 倍）和大脑皮层（多巴胺投射区域，增加 1.2 倍）中的多巴胺（DA）水平。此外，DGKη 缺乏还显著增加了大脑皮层中磷酸化多巴胺转运体（DAT）的水平（增加 1.4 倍），这会导致 DA 向突触间隙外排。此外，DG 激活并参与 DAT 磷酸化的蛋白激酶 C-β的磷酸化水平也升高了。在 Neuro-2a 细胞中表达的 DAT 将 DGKη 募集到质膜并与质膜共定位。这些结果强烈表明，大脑中 DGKη 缺乏导致的多巴胺能功能亢进导致了类似躁狂的行为。
