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首页> 外文期刊>International Journal of Molecular Sciences >Murine K2P5.1 Deficiency Has No Impact on Autoimmune Neuroinflammation due to Compensatory K2P3.1- and KV1.3-Dependent Mechanisms
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Murine K2P5.1 Deficiency Has No Impact on Autoimmune Neuroinflammation due to Compensatory K2P3.1- and KV1.3-Dependent Mechanisms

机译：小鼠K 2P 5.1缺乏对补偿性K 2P 3.1-和K V 1.3依赖性机制的自身免疫性神经炎症没有影响

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Lymphocytes express potassium channels that regulate physiological cell functions, such as activation, proliferation and migration. Expression levels of K2P5.1 (TASK2; KCNK5) channels belonging to the family of two-pore domain potassium channels have previously been correlated to the activity of autoreactive T lymphocytes in patients with multiple sclerosis and rheumatoid arthritis. In humans, K2P5.1 channels are upregulated upon T cell stimulation and influence T cell effector functions. However, a further clinical translation of targeting K2P5.1 is currently hampered by a lack of highly selective inhibitors, making it necessary to evaluate the impact of KCNK5 in established preclinical animal disease models. We here demonstrate that K2P5.1 knockout (K2P5.1−/−) mice display no significant alterations concerning T cell cytokine production, proliferation rates, surface marker molecules or signaling pathways. In an experimental model of autoimmune neuroinflammation, K2P5.1−/− mice show a comparable disease course to wild-type animals and no major changes in the peripheral immune system or CNS compartment. A compensatory upregulation of the potassium channels K2P3.1 and KV1.3 seems to counterbalance the deletion of K2P5.1. As an alternative model mimicking autoimmune neuroinflammation, experimental autoimmune encephalomyelitis in the common marmoset has been proposed, especially for testing the efficacy of new potential drugs. Initial experiments show that K2P5.1 is functionally expressed on marmoset T lymphocytes, opening up the possibility for assessing future K2P5.1-targeting drugs.
机译：淋巴细胞表达调节生理细胞功能（例如激活，增殖和迁移）的钾通道。多发性硬化和类风湿关节炎患者中，属于两孔结构域钾通道家族的K 2P 5.1（TASK2; KCNK5）通道的表达水平以前与自身反应性T淋巴细胞的活性相关。在人类中，K 2P 5.1通道在T细胞刺激后被上调并影响T细胞效应子的功能。然而，目前缺乏高选择性抑制剂阻碍了靶向K 2P 5.1的进一步临床翻译，因此有必要评估KCNK5在已建立的临床前动物疾病模型中的影响。我们在这里证明了K 2P 5.1基因敲除（K 2P 5.1 - /-）小鼠没有显示出与T细胞细胞因子的产生，增殖速率，表面标记分子或信号传导途径。在自身免疫性神经炎症的实验模型中，K 2P 5.1 - /-小鼠显示出与野生型动物相似的病程，且无重大变化在周围的免疫系统或中枢神经系统室。钾通道K 2P 3.1和K V 1.3的补偿性上调似乎抵消了K 2P 5.1的缺失。作为模拟自身免疫性神经炎症的替代模型，已提出了在普通mar猴中进行的实验性自身免疫性脑脊髓炎，特别是用于测试新的潜在药物的功效。最初的实验表明，K 2P 5.1在mar猴T淋巴细胞上有功能性表达，为评估未来的K 2P 5.1靶向药物开辟了可能性。

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