Ion channels as drug targets in the immune system

Human peripheral blood T lymphocytes possess a known complement of only three types of cation channels: a voltage-gated potassium channel, K(V)1.3, a number of small conductance calcium-activated potassium channels, K-Ca, and a store-depletion activated Ca2+ channel, CRAC. Modulation of either K(V)1.3 or CRAC has marked effects on T-cell activation. Inhibition of K(V)1.3 attenuates activation of T cells when they are stimulated either through the T-cell receptor or any other process which promotes elevation of free intracellular Ca2+ concentration. K(V)1.3 controls resting potential in T cells, and inhibition of this channel causes depolarization which reduces the electrochemical driving force for the increase in intracellular Ca2+ concentration required for cell activation. It has been shown that patients with missing or modified CRAC channels are severely immunosuppressed. Although no specific inhibitors of lymphocyte CRAC channels have been identified to date, there are both peptidyl and synthetic small molecule inhibitors of K(V)1.3 which block T cell activation in vitro. One of these peptides, margatoxin, has been shown to block a delayed-type hypersensitivity reaction in mini-pigs without toxic side effects. In addition, the homotetrameric configuration of K(V)1.3 in human T lymphocytes contrasts with the heterotetrameric form of channels in brain, where K(V)1.3 is combined with at least K(V)1.1 and K(V)1.2. Therefore, K(V)1.3 is a validated target for the development of an immunosuppressant which may have ion channel selectivity against other tissues, and which may be useful in transplantation, autoimmune disease and inflammation therapy.