Stimulation of L-type calcium channels increases tyrosine hydroxylase and dopamine in ventral midbrain cells induced from somatic cells.,STEM CELLS Translational Medicine

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Stimulation of L-type calcium channels increases tyrosine hydroxylase and dopamine in ventral midbrain cells induced from somatic cells.
STEM CELLS Translational Medicine ( IF 5.4 ) Pub Date : 2020-03-10 , DOI: 10.1002/sctm.18-0180
Malvin Jefri _{1,

2} , Scott Bell _{1,

2} , Huashan Peng _{1,

2} , Nuwan Hettige _{1,

2} , Gilles Maussion ₃ , Vincent Soubannier ₃ , Hanrong Wu _{1,

2} , Heika Silveira _{1,

2} , Jean-Francois Theroux _{1,

2} , Luc Moquin ₂ , Xin Zhang _{1,

2} , Zahia Aouabed _{1,

2} , Jeyashree Krishnan ₄ , Liam A O'Leary ₂ , Lilit Antonyan , Ying Zhang _{1,

2} , Vincent McCarty _{1,

2} , Naguib Mechawar ₂ , Alain Gratton ₂ , Andreas Schuppert ₄ , Thomas M Durcan ₃ , Edward A Fon ₃ , Carl Ernst _{1,

2}

Affiliation

Making high‐quality dopamine (DA)‐producing cells for basic biological or small molecule screening studies is critical for the development of novel therapeutics for disorders of the ventral midbrain. Currently, many ventral midbrain assays have low signal‐to‐noise ratio due to low levels of cellular DA and the rate‐limiting enzyme of DA synthesis, tyrosine hydroxylase (TH), hampering discovery efforts. Using intensively characterized ventral midbrain cells derived from human skin, which demonstrate calcium pacemaking activity and classical electrophysiological properties, we show that an L‐type calcium agonist can significantly increase TH protein levels and DA content and release. Live calcium imaging suggests that it is the immediate influx of calcium occurring simultaneously in all cells that drives this effect. Genome‐wide expression profiling suggests that L‐type calcium channel stimulation has a significant effect on specific genes related to DA synthesis and affects expression of L‐type calcium receptor subunits from the CACNA1 and CACNA2D families. Together, our findings provide an advance in the ability to increase DA and TH levels to improve the accuracy of disease modeling and small molecule screening for disorders of the ventral midbrain, including Parkinson's disease.

中文翻译：

L型钙通道的刺激增加了体细胞诱导的腹中脑细胞中的酪氨酸羟化酶和多巴胺。

制造高质量的多巴胺（DA）生产细胞用于基础生物学或小分子筛选研究，对于开发腹侧中脑疾病的新型疗法至关重要。当前，由于细胞DA水平低和DA合成的限速酶酪氨酸羟化酶（酪氨酸羟化酶）的存在，许多腹中脑测定的信噪比很低，从而阻碍了发现工作。使用从人皮肤衍生的具有特征性的腹侧中脑细胞，这些细胞表现出钙起搏活性和经典的电生理特性，我们证明L型钙激动剂可以显着增加TH蛋白水平和DA含量并释放。实时钙成像表明，直接在所有细胞中同时发生的钙大量涌入推动了这种效应。全基因组表达谱分析表明，L型钙通道刺激对与DA合成相关的特定基因有显着影响，并影响CACNA1和CACNA2D家族的L型钙受体亚基的表达。总之，我们的发现提供了提高DA和TH水平以改善疾病建模和小分子筛查腹中脑疾病（包括帕金森氏病）的准确性的能力。

更新日期：2020-03-10

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