{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T23:08:44Z","timestamp":1783724924935,"version":"3.55.0"},"reference-count":56,"publisher":"Wiley","issue":"21","license":[{"start":{"date-parts":[[2015,10,9]],"date-time":"2015-10-09T00:00:00Z","timestamp":1444348800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U54"],"award-info":[{"award-number":["U54"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2015,11]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>K<jats:sub>v<\/jats:sub>1.3 potassium channels are promising pharmaceutical targets for treating immune diseases as they modulate Ca<jats:sup>2+<\/jats:sup>signalling in T cells by regulating the membrane potential and with it the driving force for Ca<jats:sup>2+<\/jats:sup>influx. The antimycobacterial drug clofazimine has been demonstrated to attenuate antigen\u2010induced Ca<jats:sup>2+<\/jats:sup>oscillations, suppress cytokine release and prevent skin graft rejection by inhibiting K<jats:sub>v<\/jats:sub>1.3 channels with high potency and selectivity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>We used patch\u2010clamp methodology to investigate clofazimine's mechanism of action in K<jats:sub>v<\/jats:sub>1.3 channels expressed in HEK293 cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Clofazimine blocked K<jats:sub>v<\/jats:sub>1.3 channels by involving two discrete mechanisms, both of which contribute to effective suppression of channels: (i) a use\u2010dependent open\u2010channel block during long depolarizations, resulting in accelerated K<jats:sup>+<\/jats:sup>current inactivation and (ii) a block of closed deactivated channels after channels were opened by brief depolarizations. Both modes of block were use\u2010dependent and state\u2010dependent in that they clearly required prior channel opening. The clofazimine\u2010sensitive closed\u2010deactivated state of the channel was distinct from the resting closed state because channels at hyperpolarized voltages were not inhibited by clofazimine. Neither were channels in the C\u2010type inactivated state significantly affected. K<jats:sub>v<\/jats:sub>1.3 channels carrying the H399T mutation and lacking C\u2010type inactivation were insensitive to clofazimine block of the closed\u2010deactivated state, but retained their susceptibility to open\u2010channel block.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Given the prominent role of K<jats:sub>v<\/jats:sub>1.3 in shaping Ca<jats:sup>2+<\/jats:sup>oscillations, the use\u2010dependent and state\u2010dependent block of K<jats:sub>v<\/jats:sub>1.3 channels by clofazimine offers therapeutic potential for selective immunosuppression in the context of autoimmune diseases in which K<jats:sub>v<\/jats:sub>1.3\u2010expressing T cells play a significant role.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.13283","type":"journal-article","created":{"date-parts":[[2015,8,15]],"date-time":"2015-08-15T14:32:59Z","timestamp":1439649179000},"page":"5161-5173","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["State\u2010dependent blocking mechanism of K<sub>v<\/sub>1.3 channels by the antimycobacterial drug clofazimine"],"prefix":"10.1111","volume":"172","author":[{"given":"Malika","family":"Faouzi","sequence":"first","affiliation":[{"name":"Laboratory of Cell and Molecular Signaling, Center for Biomedical Research The Queen\u2018s Medical Center Honolulu HI 96813 USA"},{"name":"John A. 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