Article

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: 3.53). 02/2008; 3(12):e4009. DOI: 10.1371/journal.pone.0004009
Source: PubMed

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.

Download full-text

Full-text

Available from: Suhel Parvez, Jul 19, 2015
0 Followers
 · 
173 Views
  • Source
    • "After the graft had healed, 100 Â 10 6 human peripheral blood lymphocytes from an unrelated donor were adoptively transferred into the same animals and rejection of the skin graft was monitored. The graft was rejected within 11 days in vehicle-treated mice, but mice treated for 10 days with clofazimine did not reject the graft for 35 days, 20 days after the cessation of treatment (Ren et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Electrophysiological and pharmacological studies coupled with molecular identification have revealed a unique network of ion channels--Kv1.3, KCa3.1, CRAC (Orai1 + Stim1), TRPM7, Cl(swell)--in lymphocytes that initiates and maintains the calcium signaling cascade required for activation. The expression pattern of these channels changes during lymphocyte activation and differentiation, allowing the functional network to adapt during an immune response. The Kv1.3 channel is of interest because it plays a critical role in subsets of T and B lymphocytes implicated in autoimmune disorders. The ShK toxin from the sea anemone Stichodactyla helianthus is a potent blocker of Kv1.3. ShK-186, a synthetic analog of ShK, is being developed as a therapeutic for autoimmune diseases, and is scheduled to begin first-in-man phase-1 trials in 2011. This review describes the journey that has led to the development of ShK-186.
    Toxicon 08/2011; 59(4):529-46. DOI:10.1016/j.toxicon.2011.07.016 · 2.58 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The second messenger calcium plays an essential role in mediating the T-cell receptor (TCR) signaling pathway leading to cytokine production and T-cell clonal expansion. The immunosuppressive drugs cyclosporine A and FK506 have served both as therapeutic agents and as molecular probes for unraveling the protein phosphatase calcineurin as a rate-limiting enzyme involved in the transmission of calcium signal from the cytosol into the nucleus to reprogram gene expression. The use of mouse knockout models has helped to verify and further elucidate the functions of different isoforms of calcineurin in both helper T-cell activation and thymocyte development. In addition to calcineurin, three other classes of calmodulin-binding proteins have also been shown to play important roles in calcium signaling in T cells. Thus, Cabin1 and class II histone deacetylases have been found to constitute a novel calcium-signaling module in conjunction with the transcription factor myocyte enhance factor family and the transcriptional coactivator p300 to suppress and activate cytokine gene transcription in a calcium-dependent manner. The calmodulin-dependent protein kinases II and IV were also shown to play negative and positive regulatory functions, respectively, in TCR-mediated cytokine production. The crosstalks among these and other signal transducers in T cells form an extensive nonlinear signaling network that dictates the final outcome of the TCR signaling pathway.
    Immunological Reviews 04/2009; 228(1):184-98. DOI:10.1111/j.1600-065X.2008.00756.x · 12.91 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We discuss the potential use of inhibitors of Kv1.3 potassium channels in T lymphocytes as therapeutics for multiple sclerosis. Current treatment strategies target the immune system in a non-selective manner. The resulting general immunosuppression, toxic side-effects and increased risk of opportunistic infections create the need for more selective therapeutics. Autoreactive effector-memory T (T(EM)) cells, considered to be major mediators of autoimmunity, express large numbers of Kv1.3 channels. Selective blockers of Kv1.3 inhibit calcium signaling, cytokine production and proliferation of T(EM) cells in vitro, and T(EM) cell-motility in vivo. Kv1.3 blockers ameliorate disease in animal models of multiple sclerosis, rheumatoid arthritis, type 1 diabetes mellitus and contact dermatitis without compromising the protective immune response to acute infections. Kv1.3 blockers have a good safety profile in rodents and primates.
    Expert Opinion on Therapeutic Targets 07/2009; 13(8):909-24. DOI:10.1517/14728220903018957 · 4.90 Impact Factor
Show more

Similar Publications