University of Münster, Department of Neurology-Inflammatory Disorders of the Nervous System and Neurooncology, Münster, Germany.
Exp Neurol. 2012 Dec;238(2):149-55. doi: 10.1016/j.expneurol.2012.08.021. Epub 2012 Aug 27.
The two-pore domain potassium channel TASK1 (KCNK3) has recently emerged as an important modulator in autoimmune CNS inflammation. Previously, it was shown that T lymphocytes obtained from TASK1(-/-) mice display impaired T cell effector functions and that TASK1(-/-) mice show a significantly reduced disease severity in myelin oligodendrocyte glycoprotein (MOG(35-55)) peptide induced experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. We here evaluate a potent and specific TASK1 channel inhibitor, A293, which caused a dose-dependent reduction of T cell effector functions (cytokine production and proliferation). This effect was abolished in CD4(+) T cells from TASK1(-/-) mice but not in cells from TASK3(-/-) mice. In electrophysiological measurements, A293 application induced a significant reduction of the outward current of wildtype T lymphocytes, while there was no effect in TASK1(-/-) cells. Preventive and therapeutic application of A293 significantly ameliorated the EAE disease course in wildtype mice while it had no significant effect in TASK1(-/-) mice and was still partly effective in TASK3(-/-) mice. In summary, our findings support the concept of TASK1 as an attractive drug target for autoimmune disorders.
双孔钾通道 TASK1（KCNK3）最近被认为是自身免疫性中枢神经系统炎症的一个重要调节剂。此前有研究表明，TASK1（-/-）小鼠来源的 T 淋巴细胞表现出 T 细胞效应功能受损，而 TASK1（-/-）小鼠在髓鞘少突胶质细胞糖蛋白（MOG（35-55））肽诱导的实验性自身免疫性脑脊髓炎（EAE）中疾病严重程度显著降低，EAE 是多发性硬化症的动物模型。我们在此评估了一种有效的、特异性的 TASK1 通道抑制剂 A293，它可导致 T 细胞效应功能（细胞因子产生和增殖）呈剂量依赖性降低。这种作用在 TASK1（-/-）小鼠的 CD4（+）T 细胞中被消除，但在 TASK3（-/-）小鼠的细胞中没有被消除。在电生理测量中，A293 的应用导致野生型 T 淋巴细胞的外向电流显著降低，而在 TASK1（-/-）细胞中没有影响。预防性和治疗性应用 A293 可显著改善野生型小鼠的 EAE 病程，而在 TASK1（-/-）小鼠中没有显著影响，在 TASK3（-/-）小鼠中仍部分有效。总之，我们的研究结果支持 TASK1 作为自身免疫性疾病的一个有吸引力的药物靶点的概念。
