College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea.
College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea.
Neurochem Int. 2020 Jun;136:104726. doi: 10.1016/j.neuint.2020.104726. Epub 2020 Mar 12.
Midbrain dopaminergic (DAergic) neurotransmission plays a crucial role in regulating motor, cognitive, and emotional functions. The orphan nuclear receptor estrogen-related receptor gamma (ERRγ) is highly expressed in the adult brain and in the developing fetal brain. Our previous study showed the relevance of ERRγ in the regulation of the DAergic neuronal phenotype with the upregulation of dopamine synthesizing tyrosine hydroxylase (TH) and dopamine transporter (DAT) and the possibility that ERRγ could be a novel target for regulating DAergic neuronal differentiation. In this study, we examined whether ERRγ ligands could be small molecule regulators of DAergic phenotypes. The ERRγ agonist GSK4716 increased DAT and TH expression, and the ERRγ inverse agonist GSK5182 attenuated the retinoic acid-induced upregulation of DAT and TH in differentiated SH-SY5Y cells. We found that biphasic activation of the protein kinase A/cyclic AMP response element-binding (CREB) protein signaling pathway was involved in the GSK4716-induced increase in the DAergic phenotype in SH-SY5Y cells. CREB signaling activated as early as 3 h after GSK4716 treatment in an ERRγ-independent manner, but increased following ERRγ activation after 3 days. Protein kinase A inhibitor H-89 attenuated GSK4716-induced DAT and TH upregulation. In primary cultured DAergic neurons, GSK4716 increased neurite length and the number of DAT and TH-double-positive (DAT + TH+) neurons compared to that in control cells. These findings suggest that ERRγ ligands could serve as useful chemical tools for obtaining a better understanding of the regulation of DAergic phenotypes and might facilitate the development of small molecule therapeutics to treat DA-related neurological diseases.
中脑多巴胺能 (DAergic) 神经传递在调节运动、认知和情绪功能方面发挥着至关重要的作用。孤儿核受体雌激素相关受体 γ (ERRγ) 在成年脑中高度表达，在发育中的胎儿脑中也高度表达。我们之前的研究表明，ERRγ 在调节 DAergic 神经元表型方面具有相关性，可上调多巴胺合成酶酪氨酸羟化酶 (TH) 和多巴胺转运体 (DAT)，并且 ERRγ 可能是调节 DAergic 神经元分化的新靶点。在这项研究中，我们研究了 ERRγ 配体是否可以作为 DAergic 表型的小分子调节剂。ERRγ 激动剂 GSK4716 增加了 DAT 和 TH 的表达，ERRγ 反向激动剂 GSK5182 减弱了视黄酸诱导的分化 SH-SY5Y 细胞中 DAT 和 TH 的上调。我们发现，蛋白激酶 A/环腺苷酸反应元件结合蛋白 (CREB) 蛋白信号通路的双相激活参与了 GSK4716 诱导的 SH-SY5Y 细胞中 DAergic 表型的增加。在 ERRγ 非依赖性方式下，早在 GSK4716 处理 3 小时后就激活了 CREB 信号，但在 3 天后，随着 ERRγ 的激活，CREB 信号增加。蛋白激酶 A 抑制剂 H-89 减弱了 GSK4716 诱导的 DAT 和 TH 上调。在原代培养的 DAergic 神经元中，与对照细胞相比，GSK4716 增加了神经元突起长度以及 DAT 和 TH 双阳性 (DAT+TH+) 神经元的数量。这些发现表明，ERRγ 配体可用作深入了解 DAergic 表型调节的有用化学工具，并且可能有助于开发小分子治疗药物来治疗与 DA 相关的神经退行性疾病。
