Inhibition of T cell proliferation by selective block of Ca(2+)-activated K(+) channels.
T lymphocytes express a plethora of distinct ion channels that participate in the control of calcium homeostasis and signal transduction. Potassium channels play a critical role in the modulation of T cell calcium signaling, and the significance of the voltage-dependent K channel, Kv1.3, is well established. The recent cloning of the Ca(2+)-activated, intermediate-conductance K(+) channel (IK channel) has enabled a detailed investigation of the role of this highly Ca(2+)-sensitive K(+) channel in the calcium signaling and subsequent regulation of T cell proliferation. The role IK channels play in T cell activation and proliferation has been investigated by using various blockers of IK channels. The Ca(2+)-activated K(+) current in human T cells is shown by the whole-cell voltage-clamp technique to be highly sensitive to clotrimazole, charybdotoxin, and nitrendipine, but not to ketoconazole. Clotrimazole, nitrendipine, and charybdotoxin block T cell activation induced by signals that elicit a rise in intracellular Ca(2+)-e.g., phytohemagglutinin, Con A, and antigens such as Candida albicans and tetanus toxin in a dose-dependent manner. The release of IFN-gamma from activated T cells is also inhibited after block of IK channels by clotrimazole. Clotrimazole and cyclosporin A act synergistically to inhibit T cell proliferation, which confirms that block of IK channels affects the process downstream from T cell receptor activation. We suggest that IK channels constitute another target for immune suppression.
Jensen
B S
BS
NeuroSearch A/S, 93 Pederstrupvej DK-2750 Ballerup, Denmark. bsj@neurosearch.dk
Odum
N
N
Jorgensen
N K
NK
Christophersen
P
P
Olesen
S P
SP
D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002478:Cells, Cultured; D003022:Clotrimazole / Q000494:pharmacology; D003208:Concanavalin A / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004563:Electrochemistry; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007654:Ketoconazole / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects*; D009568:Nitrendipine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010835:Phytohemagglutinins / Q000494:pharmacology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism; D013744:Tetanus Toxin / Q000494:pharmacology; D013997:Time Factors
D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D010835:Phytohemagglutinins; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D013744:Tetanus Toxin; D003208:Concanavalin A; D007371:Interferon-gamma; D016572:Cyclosporine; D009568:Nitrendipine; D003022:Clotrimazole; D007654:Ketoconazole; D002118:Calcium