Department of Neuroscience, University Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
Neuroscience. 2011 Mar 17;177:240-51. doi: 10.1016/j.neuroscience.2010.12.057. Epub 2010 Dec 31.
In the present work we analyzed the profile of high voltage-activated (HVA) calcium (Ca2+) currents in freshly isolated striatal medium spiny neurons (MSNs) from rodent models of both idiopathic and familial forms of Parkinson's disease (PD). MSNs were recorded from reserpine-treated and 6-hydroxydopamine (6-OHDA)-lesioned rats, and from DJ-1 and PINK1 (PTEN induced kinase 1) knockout (-/-) mice. Our analysis showed no significant changes in total HVA Ca2+ current. However, we recorded a net increase in the L-type fraction of HVA Ca2+ current in dopamine-depleted rats, and of both N- and P-type components in DJ-1-/- mice, whereas no significant change in Ca2+ current profile was observed in PINK1-/- mice. Dopamine modulates HVA Ca2+ channels in MSNs, thus we also analyzed the effect of D1 and D2 receptor activation. The effect of the D1 receptor agonist SKF 83822 on Ca2+ current was not significantly different among MSNs from control animals or PD models. However, in both dopamine-depleted rats and DJ-1-/- mice the D2 receptor agonist quinpirole inhibited a greater fraction of HVA Ca2+ current than in the respective controls. Conversely, in MSNs from PINK1-/- mice we did not observe alterations in the effect of D2 receptor activation. Additionally, in both reserpine-treated and 6-OHDA-lesioned rats, the effect of quinpirole was occluded by the selective L-type Ca2+ channel blocker nifedipine, while in DJ-1-/- mice it was mostly occluded by ω-conotoxin GVIA, blocker of N-type channels. These results demonstrate that both dopamine depletion and DJ-1 deletion induce a rearrangement in the HVA Ca2+ channel profile, specifically involving those channels that are selectively modulated by D2 receptors.
在本工作中，我们分析了来自特发性和家族性帕金森病（PD）啮齿动物模型的新鲜分离纹状体中间神经元（MSNs）中高电压激活（HVA）钙（Ca2+）电流的特征。MSNs 是从利血平和 6-羟多巴胺（6-OHDA）损伤的大鼠以及 DJ-1 和 PINK1（PTEN 诱导激酶 1）敲除（-/-）小鼠中记录的。我们的分析显示，总 HVA Ca2+电流没有明显变化。然而，我们记录到多巴胺耗竭大鼠中 L 型 HVA Ca2+电流的净增加，以及 DJ-1-/-小鼠中 N-型和 P-型成分的净增加，而 PINK1-/-小鼠中 Ca2+电流特征没有明显变化。多巴胺调节 MSNs 中的 HVA Ca2+通道，因此我们还分析了 D1 和 D2 受体激活的影响。D1 受体激动剂 SKF 83822 对 Ca2+电流的影响在对照动物或 PD 模型的 MSNs 之间没有显著差异。然而，在多巴胺耗竭大鼠和 DJ-1-/-小鼠中，D2 受体激动剂喹吡罗抑制了比各自对照更大比例的 HVA Ca2+电流。相反，在 PINK1-/-小鼠的 MSNs 中，我们没有观察到 D2 受体激活的影响发生变化。此外，在利血平和 6-OHDA 损伤的大鼠中，喹吡罗的作用被选择性 L 型 Ca2+通道阻滞剂硝苯地平阻断，而在 DJ-1-/-小鼠中，它主要被 N-型通道阻断剂 ω-芋螺毒素 GVIA 阻断。这些结果表明，多巴胺耗竭和 DJ-1 缺失都会导致 HVA Ca2+通道特征的重新排列，特别是涉及到那些被 D2 受体选择性调节的通道。
