Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, Unité Mixte de Recherche-S975, Paris, France.
FASEB J. 2011 Aug;25(8):2563-73. doi: 10.1096/fj.11-182824. Epub 2011 Apr 20.
Epidemiological and experimental evidence indicates that nicotine is protective for Parkinson disease vulnerable dopamine neurons, but the underlying mechanism of this effect remains only partly characterized. To address this question, we established rat midbrain cultures maintained in experimental conditions that favor the selective and spontaneous loss of dopamine neurons. We report here that nicotine afforded neuroprotection to dopamine neurons (EC(50)=0.32 μM) but only in a situation where cytosolic Ca(2+) (Ca(2+)(cyt)) was slightly and chronically elevated above control levels by concurrent depolarizing treatments. By a pharmacological approach, we demonstrated that the rise in Ca(2+)(cyt) was necessary to sensitize dopamine neurons to the action of nicotine through a mechanism involving α-bungarotoxin-sensitive (presumably α7) nicotinic acetylcholine receptors (nAChRs) and secondarily T-type voltage-gated calcium channels. Confirming the role played by α7 nAChRs in this effect, nicotine had no protective action in midbrain cultures prepared from genetically engineered mice lacking this receptor subtype. Signaling studies revealed that Ca(2+)(cyt) elevations evoked by nicotine and concomitant depolarizing treatments served to activate a survival pathway involving the calcium effector protein calmodulin and phosphatidylinositol 3-kinase. Collectively, our data support the idea that the protective action of nicotine for dopamine neurons is activity-dependent and gated by Ca(2+)(cyt).
流行病学和实验证据表明，尼古丁对帕金森病易感的多巴胺神经元具有保护作用，但这种作用的潜在机制仍未完全阐明。为了解决这个问题，我们建立了大鼠中脑培养物，这些培养物在有利于多巴胺神经元选择性和自发性丧失的实验条件下得到维持。我们在这里报告，尼古丁为多巴胺神经元提供了神经保护（EC(50)=0.32 μM），但仅在细胞浆 Ca(2+)（Ca(2+)(cyt)）通过同时的去极化处理而略微且慢性地升高至对照水平的情况下。通过药理学方法，我们证明了 Ca(2+)(cyt)的升高对于通过涉及α-银环蛇毒素敏感（推测为α7）烟碱型乙酰胆碱受体（nAChRs）和随后的 T 型电压门控钙通道的机制使多巴胺神经元对尼古丁的作用敏感是必要的。确认 α7 nAChRs 在这种作用中所起的作用，尼古丁在缺乏这种受体亚型的基因工程小鼠的中脑培养物中没有保护作用。信号转导研究表明，尼古丁和同时的去极化处理引起的 Ca(2+)(cyt)升高用于激活涉及钙效应蛋白钙调蛋白和磷脂酰肌醇 3-激酶的存活途径。总的来说，我们的数据支持这样的观点，即尼古丁对多巴胺神经元的保护作用是依赖于活性的，并且由 Ca(2+)(cyt)调控的。
