Clofazimine Inhibits Human Kv1.3 Potassium Channel by Perturbing Calcium Oscillation in T Lymphocytes
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{"title"=>"Clofazimine inhibits human Kv1.3 potassium channel by perturbing calcium oscillation in T lymphocytes", "type"=>"journal", "authors"=>[{"first_name"=>"Yunzhao R.", "last_name"=>"Ren", "scopus_author_id"=>"23498911600"}, {"first_name"=>"Fan", "last_name"=>"Pan", "scopus_author_id"=>"55415803700"}, {"first_name"=>"Suhel", "last_name"=>"Parvez", "scopus_author_id"=>"7005455144"}, {"first_name"=>"Andrea", "last_name"=>"Fleig", "scopus_author_id"=>"7004837175"}, {"first_name"=>"Curtis R.", "last_name"=>"Chong", "scopus_author_id"=>"7202196271"}, {"first_name"=>"Jing", "last_name"=>"Xu", "scopus_author_id"=>"7407003499"}, {"first_name"=>"Yongjun", "last_name"=>"Dang", "scopus_author_id"=>"9736518100"}, {"first_name"=>"Jin", "last_name"=>"Zhang", "scopus_author_id"=>"55885598300"}, {"first_name"=>"Hongsi", "last_name"=>"Jiang", "scopus_author_id"=>"57199202343"}, {"first_name"=>"Reinhold", "last_name"=>"Penner", "scopus_author_id"=>"7103238368"}, {"first_name"=>"Jun O.", "last_name"=>"Liu", "scopus_author_id"=>"7410103307"}], "year"=>2008, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "pui"=>"354011929", "doi"=>"10.1371/journal.pone.0004009", "sgr"=>"58049211941", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "pmid"=>"19104661", "scopus"=>"2-s2.0-58049211941"}, "id"=>"08d1b12d-aee9-3bf3-8cc5-28a0713b48f2", "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.", "link"=>"http://www.mendeley.com/research/clofazimine-inhibits-human-kv13-potassium-channel-perturbing-calcium-oscillation-t-lymphocytes", "reader_count"=>61, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>5, "Researcher"=>19, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>11, "Student > Postgraduate"=>3, "Student > Master"=>8, "Other"=>6, "Student > Bachelor"=>2, "Lecturer"=>1, "Professor"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>5, "Researcher"=>19, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>11, "Student > Postgraduate"=>3, "Student > Master"=>8, "Other"=>6, "Student > Bachelor"=>2, "Lecturer"=>1, "Professor"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>5, "Biochemistry, Genetics and Molecular Biology"=>6, "Medicine and Dentistry"=>14, "Agricultural and Biological Sciences"=>23, "Neuroscience"=>2, "Pharmacology, Toxicology and Pharmaceutical Science"=>6, "Physics and Astronomy"=>1, "Chemistry"=>2, "Social Sciences"=>1, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>14}, "Neuroscience"=>{"Neuroscience"=>2}, "Chemistry"=>{"Chemistry"=>2}, "Social Sciences"=>{"Social Sciences"=>1}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>23}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>6}, "Unspecified"=>{"Unspecified"=>5}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>6}}, "reader_count_by_country"=>{"Netherlands"=>1, "United States"=>4, "Taiwan"=>1, "Spain"=>1}, "group_count"=>5}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/452437", "https://ndownloader.figshare.com/files/452454", "https://ndownloader.figshare.com/files/452460", "https://ndownloader.figshare.com/files/452475", "https://ndownloader.figshare.com/files/452504", "https://ndownloader.figshare.com/files/452525", "https://ndownloader.figshare.com/files/452545", "https://ndownloader.figshare.com/files/452570", "https://ndownloader.figshare.com/files/452600"], "description"=>"<div><p>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 <em>in vivo</em>. Together, these results suggest that clofazimine is a promising immunomodulatory drug candidate for treating a variety of autoimmune disorders.</p></div>", "links"=>[], "tags"=>["clofazimine", "inhibits", "potassium", "perturbing", "calcium", "oscillation", "lymphocytes"], "article_id"=>149114, "categories"=>["Immunology", "Biochemistry", "Pharmacology"], "users"=>["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"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0004009.s001", "https://dx.doi.org/10.1371/journal.pone.0004009.s002", "https://dx.doi.org/10.1371/journal.pone.0004009.s003", "https://dx.doi.org/10.1371/journal.pone.0004009.s004", "https://dx.doi.org/10.1371/journal.pone.0004009.s005", "https://dx.doi.org/10.1371/journal.pone.0004009.s006", "https://dx.doi.org/10.1371/journal.pone.0004009.s007", "https://dx.doi.org/10.1371/journal.pone.0004009.s008", "https://dx.doi.org/10.1371/journal.pone.0004009.s009"], "stats"=>{"downloads"=>0, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Clofazimine_Inhibits_Human_Kv1_3_Potassium_Channel_by_Perturbing_Calcium_Oscillation_in_T_Lymphocytes/149114", "title"=>"Clofazimine Inhibits Human Kv1.3 Potassium Channel by Perturbing Calcium Oscillation in T Lymphocytes", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2008-12-23 02:31:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/913555"], "description"=>"<p>(A) Averaged time course of Kv1.3 currents measured in Jurkat T cells in the absence and the presence of clofazimine (CLF) or margatoxin (MGX). Various concentrations of CLF (n = 5 each) or 10 nM MGX (open squares, n = 5) were applied as indicated by the black bar. Currents were elicited by applying a ramp protocol from −100 mV to +100 mV over a span of 50 ms and acquired every 2 s. Holding potential was −80 mV. Current amplitudes were extracted at +80 mV and plotted versus the time of the experiment. Currents were normalized to cell size and plotted as pA/pF. Error bars indicate S.E.M. (B) Current-voltage relationship of Kv1.3 currents taken from example cells and extracted before (30 s) or after application (120 s) of either 10 µM CLF (thick trace) or 10 nM MGX (thin trace). (C) Dose-response curve of the inhibitory effect of CLF (closed circles, n = 5 each). Data were normalized to the current measured before application at 30 s as I/I<sub>30s</sub>. The inhibition was measured at the end of application at 120 s. A dose-response fit to the data resulted in an IC<sub>50</sub> of 300 nM and a Hill coefficient of 0.75. The maximum inhibitory effect of CLF was compared to the inhibitory effect of 10 nM MGX (open circle, n = 5), a saturating concentration to assure Kv1.3 inhibition. The dashed line indicates the maximum inhibitory effect of MGX. (D) Clofazimine inhibits Kv1.3 in primary human T cells. Average development of Kv1.3 currents measured in human T cells (protocol approval number RIRC QMC RA-2004-048) in control cells (closed circles, n = 5) and with superfusion of external standard solution supplemented with 1 µM clofazimine (open circles, n = 5) as indicated by the black bar. Error bars indicate S.E.M. Data were normalized to the time of application, averaged and plotted versus time of the experiment. Holding potential was −80 mV. Voltage ramp protocol and solutions are described in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0004009#s4\" target=\"_blank\">methods</a>. (E) Current behavior of heterologous mouse Kv1.3 expressed in L929 cells plotted over time in response to increasing concentrations of clofazimine, applied through a wide-mouth glass pipette at the time indicated by the black bar (control, closed circles, no application, n = 7; 10 µM, closed triangles, n = 4; 1 µM, open square, n = 6; 100 nM, open circles, n = 5). Currents were measured by application of a ramp protocol from −100 mV to +100 mV over 500 ms and given at 5 s intervals. Current amplitudes were assessed at +80 mV, normalized to the current amplitude at 40 s, averaged and plotted versus time. Error bars indicate S.E.M. (F) I/V curve of a representative cell expressing mouse Kv1.3 with control I/V (black) extracted at 40 s after whole-cell establishment and the I/V for 10 µM clofazimine extracted at the end of application (red, 160 s). (G) Concentration-response behavior of mouse Kv1.3 expressed in L929 cells to increasing concentrations of clofazimine (n = 4–7). A fit to the data gave an IC<sub>50</sub> of 470 nM with a Hill coefficient of 0.5.</p>", "links"=>[], "tags"=>["inhibits"], "article_id"=>584006, "categories"=>["Immunology", "Biochemistry", "Pharmacology"], "users"=>["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"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0004009.g003", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Clofazimine_inhibits_Kv1_3_channel_/584006", "title"=>"Clofazimine inhibits Kv1.3 channel.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-12-23 01:06:46"}
  • {"files"=>["https://ndownloader.figshare.com/files/913348"], "description"=>"<p>(A) Clofazimine (structure shown in inset) inhibits IL-2 proximal promoter driven-luciferase stimulated by PMA/ionomycin in Jurkat T cells (n = 6). The IC<sub>50</sub>s for reporter assay is 21.8±4.4 nM. (B) Clofazimine inhibits IL-2 production in PMA/thapsigargin-stimulated Jurkat T cells (IC<sub>50</sub> = 1.10±0.26 µM) and human mixed lymphocyte reaction (MLR) (IC<sub>50</sub> = 0.90±0.17 µM) (n = 6 each). (C) Clofazimine inhibits NFAT pathway in Jurkat T cells. The IC<sub>50</sub>s of clofazimine in the IL-2, NFAT, NF-κB luciferase reporter assays are 56.0±14.8 nM, 113±30 nM and 2.43±1.25 µM, respectively (n = 6 each). Both reporters were stimulated with PMA/ionomycin. (D) Clofazimine significantly enhances AP-1 luciferase reporter at high concentrations (>1 µM, n = 6). The reporter was also activated by PMA/ionomycin. (E) Clofazimine inhibits dephosphorylation of endogenous NFATc2 in response to ionomycin treatment. NFATc2 and α-tubulin were detected by Western blot using specific antibodies.</p>", "links"=>[], "tags"=>["inhibits", "il-2", "nfat", "activation", "jurkat"], "article_id"=>583791, "categories"=>["Immunology", "Biochemistry", "Pharmacology"], "users"=>["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"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0004009.g001", "stats"=>{"downloads"=>2, "page_views"=>23, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Clofazimine_inhibits_IL_2_production_and_NFAT_activation_in_Jurkat_T_cells_/583791", "title"=>"Clofazimine inhibits IL-2 production and NFAT activation in Jurkat T cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-12-23 01:03:11"}
  • {"files"=>["https://ndownloader.figshare.com/files/913477"], "description"=>"<p>(A) Calcium influx was inhibited by clofazimine in a heterogeneous fashion. Clofazimine was added 5 minutes before stimulation with 1 µM TG. Representative images were taken 30 minutes after 2 mM calcium was added. The color gradient represents fura-2 350 nm/380 nm excitation ratio. (B) Effects of clofazimine on store-depletion induced calcium influx. Typically the cells can be divided into 2 groups, the responsive (red) and none-responsive (pink) populations. Each curve represents average signal of 20 cells from the same field in (A) (The results were reproduced 10 times under the same condition). (C) Effect of clofazimine on calcium oscillation in Jurkat T cells (representative of 56 cells). The oscillation was stimulated by 10 nM TG. (D) Clofazimine elongated oscillation period in more than 80% of Jurkat T cells (Results represented 3 experiments, at least 80 cells were counted for each experiment).</p>", "links"=>[], "tags"=>["interferes", "calcium", "influx", "jurkat"], "article_id"=>583920, "categories"=>["Immunology", "Biochemistry", "Pharmacology"], "users"=>["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"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0004009.g002", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Clofazimine_interferes_with_calcium_influx_in_Jurkat_T_cells_/583920", "title"=>"Clofazimine interferes with calcium influx in Jurkat T cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-12-23 01:05:20"}
  • {"files"=>["https://ndownloader.figshare.com/files/913895"], "description"=>"<p>(A) Representative skin grafts at different days post-transplantation. Human foreskin was transplanted onto Pfp/Rag2−/− mice. 1.0×10<sup>8</sup> human peripheral blood lymphocytes (PBL) were adoptively transferred into each animal at Day 7 post-transplantation. Administration of clofazimine or carrier control (olive oil) was also initiated at Day 7. * Days after skin transplantation/cell transfer. (B) Effect of clofazimine on the mean survival time of transplanted human (n = 5) and mouse (n = 4) skin grafts. The mouse skin transplantation was performed using Balb/c mice as skin donors, B6 Rag1−/− mice as recipients and PBL from B6 for adoptive transfer.</p>", "links"=>[], "tags"=>["inhibits", "cell-mediated", "graft", "rejection", "immunodeficient"], "article_id"=>584344, "categories"=>["Immunology", "Biochemistry", "Pharmacology"], "users"=>["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"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0004009.g006", "stats"=>{"downloads"=>3, "page_views"=>29, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Clofazimine_inhibits_human_T_cell_mediated_skin_graft_rejection_in_immunodeficient_mice_/584344", "title"=>"Clofazimine inhibits human T cell-mediated skin graft rejection in immunodeficient mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-12-23 01:12:24"}
  • {"files"=>["https://ndownloader.figshare.com/files/913702"], "description"=>"<p>(A) Clofazimine colocalizes with Kv1.3 on the plasma membrane of Jurkat T cells. Clofazimine was visualized in FITC channel while Kv1.3 was stained by Cy5 secondary antibody. (B) SDS-PAGE analysis of His-Kv1.3 purified from 293 T cells upon staining with Coomassie blue. Recombinant Kv1.3 protein was found in the 200 and 300 mM imidazole elution fractions. (C) Gel shift of clofazimine by Kv1.3 on native polyacrylamide gel. 10 µM Clofazimine was incubated with buffer alone (lane 1), 2 µM BSA (lane 2) and 2 µM Kv1.3 (lane 3) for 30 minutes before the samples were resolved on a native polyacrylamide gel. Proteins and clofazimine were transferred to nitrocellulose membrane. The presence of clofazimine was apparent by its intense organge/yellow color (member picture) and Kv1.3 was detected by Western blot analysis. The membrane image was taken in the same field after HRP detection was completed.</p>", "links"=>[], "tags"=>["clofazimine"], "article_id"=>584152, "categories"=>["Immunology", "Biochemistry", "Pharmacology"], "users"=>["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"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0004009.g004", "stats"=>{"downloads"=>0, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Interaction_between_clofazimine_and_Kv1_3_in_vivo_and_in_vtro_/584152", "title"=>"Interaction between clofazimine and Kv1.3 <i>in vivo</i> and <i>in vtro.</i>", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-12-23 01:09:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/913785"], "description"=>"<p>Over-expression of Kv1.3 in Jurkat T cells resulted in resistance of the IL-2 luciferase reporter to CLF. The IC<sub>50</sub>s for different curves (Kv1.3 overexpression from low to high) are 41.6±8.4 nM, 41.0±14.5 nM, 386±214 nM, 1.37±0.52 µM and 1.46±0.63 µM (n = 6). (B) Kv1.3 knockdown resulted in an increase in sensitivity of the IL-2 luciferase reporter to CLF. The IC<sub>50</sub>s for control EGFP-siRNA lentiviral transduced Jurkat T cells (control) was 49.9±13.0 nM, while that for shKv1.3-4 transduced cells was 10.5±2.4 nM (n = 6). (C) Lentivirus-mediated knockdown of Kv1.3 assessed by Western blot. (D) Quantitation of Kv1.3 knockdown efficiency. After normalization against GAPDH, lenti-Kv1.3-4 decreased Kv1.3 protein level by 70% in comparison to the control (Lenti-EGFP).</p>", "links"=>[], "tags"=>["chemical biology", "immunology/leukocyte signaling and gene expression", "pharmacology/drug development"], "article_id"=>584230, "categories"=>["Immunology", "Biochemistry", "Pharmacology"], "users"=>["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"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0004009.g005", "stats"=>{"downloads"=>2, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_A_/584230", "title"=>"(A)", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-12-23 01:10:30"}

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Relative Metric

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