脆性 X 智力低下蛋白缺失的人源和鼠源神经前体细胞中 L 型钙通道钙内流增加。
Increased Calcium Influx through L-type Calcium Channels in Human and Mouse Neural Progenitors Lacking Fragile X Mental Retardation Protein.
机构信息
Faculty of Medicine, Physiology, University of Helsinki, PO Box 63, FIN-00014 University of Helsinki, Helsinki, Finland.
Array and Analysis Facility, Department of Medical Sciences, Uppsala University, PO Box 3056, 75003 Uppsala, Sweden.
出版信息
Stem Cell Reports. 2018 Dec 11;11(6):1449-1461. doi: 10.1016/j.stemcr.2018.11.003. Epub 2018 Nov 29.
The absence of FMR1 protein (FMRP) causes fragile X syndrome (FXS) and disturbed FMRP function is implicated in several forms of human psychopathology. We show that intracellular calcium responses to depolarization are augmented in neural progenitors derived from human induced pluripotent stem cells and mouse brain with FXS. Increased calcium influx via nifedipine-sensitive voltage-gated calcium (Ca) channels contributes to the exaggerated responses to depolarization and type 1 metabotropic glutamate receptor activation. The ratio of L-type/T-type Ca channel expression is increased in FXS progenitors and correlates with enhanced progenitor differentiation to glutamate-responsive cells. Genetic reduction of brain-derived neurotrophic factor in FXS mouse progenitors diminishes the expression of Ca channels and activity-dependent responses, which are associated with increased phosphorylation of the phospholipase C-γ1 site within TrkB receptors and changes of differentiating progenitor subpopulations. Our results show developmental effects of increased calcium influx via L-type Ca channels in FXS neural progenitors.
FMR1 蛋白缺失会导致脆性 X 综合征（FXS），而 FMRP 功能障碍与多种形式的人类精神病理学有关。我们发现，源自人类诱导多能干细胞和 FXS 小鼠大脑的神经祖细胞中，去极化引起的细胞内钙反应增强。通过硝苯地平敏感的电压门控钙（Ca）通道增加钙内流有助于对去极化和 1 型代谢型谷氨酸受体激活的过度反应。FXS 祖细胞中 L 型/T 型 Ca 通道表达的比值增加，与增强祖细胞向谷氨酸反应性细胞的分化相关。FXS 小鼠祖细胞中脑源性神经营养因子的基因减少会降低 Ca 通道的表达和活性依赖性反应，这与 TrkB 受体中 PLC-γ1 位点的磷酸化增加以及分化祖细胞亚群的变化有关。我们的结果表明，在 FXS 神经祖细胞中，通过 L 型 Ca 通道增加钙内流会产生发育效应。
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