Stage-specific distinctions in potassium channel blocker control of T-lymphocyte activation.
Effects of four known blockers of T-lymphocyte potassium channels [verapamil, quinine, 4-aminopyridine (4-AP) and tetraethylammonium (TEA)], were studied on polyclonal T-cell activation induced by two plant mitogens (phytohemmaglutinin; PHA and concanavalin A; ConA), a mitogenic anti-Thy 1.2 monoclonal antibody (mAb G7) and phorbol ester (phorbol myristate acetate; PMA). Potassium channel blockers blocked all four modes of T-cell activation in a dose-dependent fashion with the same rank order of potency (verapamil greater than quinine greater than 4-AP greater than TEA). Kinetic studies of the timing of potassium channel blocker effect, indicated that, while 4-AP and TEA interfere only with early events of T-cell activation, verapamil and quinine can also interfere with later steps of T-cell mitogenesis. This notion was confirmed by studies of interleukin 2(IL-2)-directed activated T-cell growth. Verapamil and quinine blocked this late step in different types of activated T-cells with the same potency they blocked induction of resting T-cell mitogenesis. On the other hand, 4-AP and TEA, at maximal inhibitory doses for resting T-cells, showed little or no effect at IL-2-directed growth. Kinetic studies of the timing of quinine effect showed that the target of quinine action on activated T-cells is critically involved in IL-2 signalling within the first 2-4 h of IL-2 addition. These studies suggest that, besides the voltage-gated potassium channel previously described, a second target for verapamil and quinine action controls IL-2-derived signals to activated T-cells.
Dos Reis
G A
GA
Department of Immunology, Federal University of Rio de Janeiro, Brazil.
Nóbrega
A F
AF
Persechini
P M
PM
D015761:4-Aminopyridine; D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008934:Mitogens / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*; D011803:Quinine / Q000494:pharmacology; D011975:Receptors, Mitogen / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects*; D013757:Tetraethylammonium Compounds / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
D000631:Aminopyridines; D008934:Mitogens; D015221:Potassium Channels; D011975:Receptors, Mitogen; D013757:Tetraethylammonium Compounds; D011803:Quinine; D015761:4-Aminopyridine; D014700:Verapamil