Dopamine induces apoptosis in young, but not in neonatal, neurons via Ca2+-dependent signal
Dopamine induces apoptosis in young, but not in neonatal, neurons via Ca2+-dependent signal
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DOI：
10.1152/ajpcell.00088.2007
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发表时间：
2007-11-01
影响因子：
5.5
通讯作者：
Ishikawa, Yoshihiro
中科院分区：
文献类型：
--
作者：
Iwatsubo, Kousaku;Suzuki, Sayaka;Ishikawa, Yoshihiro
多巴胺信号在神经元凋亡的调控中起重要作用。在出生后，多巴胺信号在纹状体中发生了巨大的变化。然而，由于出生后很难培养神经元，因此对多巴胺介导的细胞凋亡的发育变化知之甚少。为了观察这种变化，我们建立了2 ~ 3周龄小鼠纹状体神经元原代培养方法。多巴胺通过d -1样受体诱导幼鼠纹状体神经元凋亡，而非新生鼠纹状体神经元，这表明多巴胺对细胞凋亡的影响随着发育而改变。相比之下，尽管异丙肾上腺素（Iso），一种β -肾上腺素能受体激动剂，比多巴胺更能增加cAMP的产生，但Iso并没有增加幼鼠和新生小鼠纹状体神经元的凋亡，这表明cAMP在多巴胺介导的细胞凋亡中起次要作用。接下来，我们研究了多巴胺对Ca2+信号的影响。多巴胺（而非Iso）显著增加了幼鼠纹状体神经元细胞内Ca2+， Ca2+螯合剂消除了多巴胺诱导的细胞凋亡，表明Ca2+在多巴胺介导的细胞凋亡途径中发挥了重要作用。相比之下，多巴胺未能增加新生儿神经元细胞内Ca2+，而PLC的表达，可以通过d -1样受体激活增加细胞内Ca2+，在年轻的显著高于新生儿纹状体神经元。这些数据表明，多巴胺介导的Ca2+信号的发育变化是幼纹状体和新生儿纹状体诱导凋亡差异的原因。此外，年轻纹状体神经元的培养是可行的，并可能为发育研究提供新的工具。
Dopamine signaling plays a major role in regulation of neuronal apoptosis. During the postnatal period, dopamine signaling is known to be dramatically changed in the striatum. However, because it is difficult to culture neurons after birth, little is known about developmental changes in dopamine-mediated apoptosis. To examine such changes, we established the method of primary culture of striatal neurons from 2- to 3-wk-old ( young) mice. Dopamine, via D-1-like receptors, induced apoptosis in young, but not neonatal, striatal neurons, suggesting that the effect of dopamine on apoptosis changed with development. In contrast, although isoproterenol (Iso), a beta-adrenergic receptor agonist, increased cAMP production to a greater degree than dopamine, Iso did not increase apoptosis in striatal neurons from young and neonatal mice, suggesting a minor role of cAMP in dopamine-mediated apoptosis. Next, we examined the effect of dopamine on Ca2+ signaling. Dopamine, but not Iso, markedly increased intracellular Ca2+ in striatal neurons from young mice, and Ca2+-chelating agents abolished dopamine-induced apoptosis, suggesting that Ca2+ played a major role in the dopamine-mediated apoptosis pathway. In contrast, dopamine failed to increase intracellular Ca2+ in neonatal neurons, and the expression of PLC, which can increase intracellular Ca2+ via D-1-like receptor activation, was significantly greater in young than in neonatal striatal neurons. These data suggest that the developmental change in dopamine-mediated Ca2+ signaling was responsible for differences between young and neonatal striatum in induction of apoptosis. Furthermore, the culture of young striatal neurons is feasible and may provide a new tool for developmental studies.