Clofazimine inhibits human Kv1.3 potassium channel by perturbing calcium oscillation in T lymphocytes.
Clofazimine inhibits human Kv1.3 potassium channel by perturbing calcium oscillation in T lymphocytes.
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DOI：
10.1371/journal.pone.0004009
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发表时间：
2008
期刊：
影响因子：
3.7
通讯作者：
Liu, Jun O.
中科院分区：
文献类型：
--
作者：
Ren, Yunzhao R.;Pan, Fan;Parvez, Suhel;Fleig, Andrea;Chong, Curtis R.;Xu, Jing;Dang, Yongjun;Zhang, Jin;Jiang, Hongsi;Penner, Reinhold;Liu, Jun O.
Kv1.3钾通道在效应记忆T细胞中起着重要作用，并与几种重要的自身免疫性疾病有关，包括多发性硬化症、银屑病和1型糖尿病。已经报道了许多有效的Kv1.3通道的小分子抑制剂，其中一些在各种自身免疫性疾病的动物模型中被发现是有效的。我们在此报告的识别氯法齐明，一种已知的抗分枝杆菌药物，作为一种新的抑制剂的人Kv1.3。氯法齐明最初是从Johns霍普金斯药物库筛选中被鉴定为细胞内T细胞受体介导的信号传导的抑制剂，该信号传导导致T细胞中人白细胞介素-2基因的转录激活。一个系统的机械解卷积显示，氯法齐明选择性地阻断Kv1.3通道的活性，干扰钙释放激活的钙通道的振荡频率，这反过来又导致抑制钙调神经磷酸酶-NFAT信号通路。氯法齐明的这些作用提供了支持Kv1.3和人T细胞钙振荡之间因果关系的一线实验证据。此外，在体内动物模型中，发现氯法齐明可有效阻断人T细胞介导的皮肤移植排斥反应。总之，这些结果表明，氯法齐明是一个有前途的免疫调节药物候选治疗各种自身免疫性疾病。
The Kv1.3 potassium channel plays an essential role in effector memory T cells and has been implicated in several important autoimmune diseases including multiple sclerosis, psoriasis and type 1 diabetes. A number of potent small molecule inhibitors of Kv1.3 channel have been reported, some of which were found to be effective in various animal models of autoimmune diseases. We report herein the identification of clofazimine, a known anti-mycobacterial drug, as a novel inhibitor of human Kv1.3. Clofazimine was initially identified as an inhibitor of intracellular T cell receptor-mediated signaling leading to the transcriptional activation of human interleukin-2 gene in T cells from a screen of the Johns Hopkins Drug Library. A systematic mechanistic deconvolution revealed that clofazimine selectively blocked the Kv1.3 channel activity, perturbing the oscillation frequency of the calcium-release activated calcium channel, which in turn led to the inhibition of the calcineurin-NFAT signaling pathway. These effects of clofazimine provide the first line of experimental evidence in support of a causal relationship between Kv1.3 and calcium oscillation in human T cells. Furthermore, clofazimine was found to be effective in blocking human T cell-mediated skin graft rejection in an animal model in vivo. Together, these results suggest that clofazimine is a promising immunomodulatory drug candidate for treating a variety of autoimmune disorders.
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DOI：
10.1084/jem.160.2.369
发表时间：
1984-08-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Chandy KG;DeCoursey TE;Cahalan MD;McLaughlin C;Gupta S
通讯作者：
Gupta S
影响因子：
64.8
作者：
DECOURSEY, TE;CHANDY, KG;CAHALAN, MD
通讯作者：
CAHALAN, MD
影响因子：
4
作者：
Chong, Curtis R.;Xu, Jing;Liu, Jun O.
通讯作者：
Liu, Jun O.
影响因子：
--
作者：
Griffith, EC;Su, Z;Liu, JO
通讯作者：
Liu, JO
影响因子：
3.1
作者：
AFDHAL, NH;LONG, A;ODONOGHUE, DP
通讯作者：
ODONOGHUE, DP