Clofazimine Inhibits Human Kv1.3 Potassium Channel by Perturbing Calcium Oscillation in T Lymphocytes

Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
PLoS ONE (Impact Factor: 3.23). 02/2008; 3(12):e4009. DOI: 10.1371/journal.pone.0004009
Source: PubMed


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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    • "It has been recently employed in combination with other anti-mycobacterial drugs to treat Mycobacterium avium infections in AIDS patients (Kemper et al., 1992)(Kemper et al., 1992) The immunosuppressive effects of clofazimine are widely reported in animal models (Bezerra et al., 2005; Zeis & Anderson, 1986). A recent systematic study of clofazimine with human T cells revealed that this drug actually is a Kv1.3 (KCNA3) channel blocker (Ren et al., 2008)(Ren et al., 2008) Kv1.3 potassium channel has emerged as an attractive focus for development of immunosuppressive drugs the channel plays a key role in activation and function of T cells and is crucial in many important autoimmune disorders. With time the new attributes and functions of clofazimine have been disclosed. "
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    • "The selective action of these drugs on tumor cells is related to a synergistic effect of a higher expression of Kv1.3 and of an altered redox state of cancer cells. The fact that clofazimine is already used in the clinic for the treatment of e.g., leprosis (Ren et al., 2008) and shows an excellent safety profile supports the feasibility of targeting mtKv1.3 for therapy. "
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    • "Most specific Kv1.3 blockers, including MgTX, are not blood brain barrier permeable, and thus have limited clinical usage. Clofazimine is a known anti-mycobacterial drug and recently was found to inhibit the Kv1.3 channel [34]. It readily penetrates the blood brain barrier and reaches the brain in concentrations sufficient to completely protect against GrB-mediated neurotoxicity as observed in our in vivo studies. "
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