Clofazimine inhibits human Kv1.3 potassium channel by perturbing calcium oscillation in T lymphocytes.
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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2008-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC2602975?pdf=render |
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| author | Yunzhao R Ren Fan Pan Suhel Parvez Andrea Fleig Curtis R Chong Jing Xu Yongjun Dang Jin Zhang Hongsi Jiang Reinhold Penner Jun O Liu |
| author_facet | Yunzhao R Ren Fan Pan Suhel Parvez Andrea Fleig Curtis R Chong Jing Xu Yongjun Dang Jin Zhang Hongsi Jiang Reinhold Penner Jun O Liu |
| author_sort | Yunzhao R Ren |
| collection | DOAJ |
| description | 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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| id | doaj.art-2c1a66d90db34a0980ff64e7c88a241c |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-12T22:56:32Z |
| publishDate | 2008-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-2c1a66d90db34a0980ff64e7c88a241c2022-12-22T03:13:11ZengPublic Library of Science (PLoS)PLoS ONE1932-62032008-01-01312e400910.1371/journal.pone.0004009Clofazimine inhibits human Kv1.3 potassium channel by perturbing calcium oscillation in T lymphocytes.Yunzhao R RenFan PanSuhel ParvezAndrea FleigCurtis R ChongJing XuYongjun DangJin ZhangHongsi JiangReinhold PennerJun O LiuThe 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.http://europepmc.org/articles/PMC2602975?pdf=render |
| spellingShingle | Yunzhao R Ren Fan Pan Suhel Parvez Andrea Fleig Curtis R Chong Jing Xu Yongjun Dang Jin Zhang Hongsi Jiang Reinhold Penner Jun O Liu Clofazimine inhibits human Kv1.3 potassium channel by perturbing calcium oscillation in T lymphocytes. PLoS ONE |
| title | Clofazimine inhibits human Kv1.3 potassium channel by perturbing calcium oscillation in T lymphocytes. |
| title_full | Clofazimine inhibits human Kv1.3 potassium channel by perturbing calcium oscillation in T lymphocytes. |
| title_fullStr | Clofazimine inhibits human Kv1.3 potassium channel by perturbing calcium oscillation in T lymphocytes. |
| title_full_unstemmed | Clofazimine inhibits human Kv1.3 potassium channel by perturbing calcium oscillation in T lymphocytes. |
| title_short | Clofazimine inhibits human Kv1.3 potassium channel by perturbing calcium oscillation in T lymphocytes. |
| title_sort | clofazimine inhibits human kv1 3 potassium channel by perturbing calcium oscillation in t lymphocytes |
| url | http://europepmc.org/articles/PMC2602975?pdf=render |
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