Lymphocyte ion channels as a target for immunosuppression

Abstract

Lymphocytes possess a plethora of distinct ion channels whose activities are important for controlling calcium homeostasis and signal transduction processes in these cells. Among those that have been identified by electrophysiological techniques are several different types of voltage-gated potassium channels, calcium-activated potassium channels, chloride channels and mitogen-regulated calcium channels. Functioning together, these ion channels regulate lymphocyte activation, mitogenesis and cell volume. The expression of the various potassium channels is species dependent. In human peripheral T cells, four types of potassium channels are found: a voltage-dependent channel, which is a member of theShaker family and the product of the Kv1.3 gene, and three distinct small conductance calcium-activated potassium channels. Inhibition of the Kv1.3 channel by selective peptidyl inhibitors (e.g., margatoxin) causes depolarization of human T cells, indicating that the activity of this channel controls the resting plasma membrane potential of lymphocytes. Depolarization of T cells specifically blocks calcium-dependent pathways controlling lymphokine production and cell proliferation, without having significant effects on calcium-independent T-cell responses. Therefore, it is expected that selective small-molecule inhibitors of Kv1.3 will function as novel immunosuppressant agents.