TY - JOUR

T1 - Inhibition of T cell proliferation by selective block of Ca(2+)-activated K(+) channels

AU - Jensen, B S

AU - Odum, Niels

AU - Jorgensen, N K

AU - Christophersen, P

AU - Olesen, Søren-Peter

N1 - Keywords: Calcium; Calcium Channel Blockers; Cells, Cultured; Clotrimazole; Concanavalin A; Cyclosporine; Dose-Response Relationship, Drug; Electrochemistry; Enzyme Inhibitors; Growth Inhibitors; Humans; Interferon-gamma; Ketoconazole; Lymphocyte Activation; Nitrendipine; Patch-Clamp Techniques; Phytohemagglutinins; Potassium Channel Blockers; Potassium Channels; T-Lymphocytes; Tetanus Toxin; Time Factors

PY - 1999

Y1 - 1999

N2 - 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.

AB - 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.

M3 - Journal article

C2 - 10485926

VL - 96

SP - 10917

EP - 10921

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 19

ER -