title: Clofazimine inhibits human Kv1.3 potassium channel by perturbing calcium oscillation in T lymphocytes.
abstract: 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.
authors.affiliation: Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Yunzhao R
authors.initials: YR
authors.lastname: Ren
authors.forename: Fan
authors.initials: F
authors.lastname: Pan
authors.forename: Suhel
authors.initials: S
authors.lastname: Parvez
authors.forename: Andrea
authors.initials: A
authors.lastname: Fleig
authors.forename: Curtis R
authors.initials: CR
authors.lastname: Chong
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Dang
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.forename: Hongsi
authors.initials: H
authors.lastname: Jiang
authors.forename: Reinhold
authors.initials: R
authors.lastname: Penner
authors.forename: Jun O
authors.initials: JO
authors.lastname: Liu
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects* / Q000276:immunology; D002478:Cells, Cultured; D002991:Clofazimine / Q000378:metabolism / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007155:Immunologic Factors / Q000378:metabolism / Q000494:pharmacology; D007376:Interleukin-2 / Q000378:metabolism; D019169:Jurkat Cells; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D050778:NFATC Transcription Factors / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization / Q000187:drug effects; D016038:Skin Transplantation / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D014162:Transfection
chemical_list: D000900:Anti-Bacterial Agents; D007155:Immunologic Factors; D007376:Interleukin-2; D051664:Kv1.3 Potassium Channel; D050778:NFATC Transcription Factors; D002991:Clofazimine