Potassium Channel Blockade by the Sea Anemone Toxin ShK for the Treatment of Multiple Sclerosis and Other Autoimmune Diseases

Abstract

Expression of the two lymphocyte potassium channels, the voltage-gated channel Kv1.3 and the calcium activated channel IKCa1, changes during differentiation of human T cells. While IKCa1 is the functionally dominant channel in naïve and “early” memory T cells, Kv1.3 is crucial for the activation of terminally differentiated effector memory (TEM) T cells. Because of the involvement of TEM cells in autoimmune processes, Kv1.3 is regarded as a promising target for the treatment of T-cell mediated autoimmune diseases such as multiple sclerosis and the prevention of chronic transplant rejection. ShK, a 35- residue polypeptide toxin from the sea anemone, Stichodactyla helianthus, blocks Kv1.3 at low picomolar concentrations. ShK adopts a central helix-kink-helix fold, and alanine-scanning and other mutagenesis studies have defined its channel-binding surface. Models have been developed of how this toxin effects K+- channel blockade and how its docking configuration might differ in ShK-Dap22, which contains a single side chain substitution that confers specificity for Kv1.3 blockade. ShK, ShK-Dap22 and the Kv1.3 blocking scorpion toxin kaliotoxin have been shown to prevent and treat experimental autoimmune encephalomyelitis in rats, a model for multiple sclerosis. A fluoresceinated analog of ShK, ShK-F6CA, has been developed, which allows the detection of activated TEM cells in human and animal blood samples by flow cytometry and the visualization of Kv1.3 channel distribution in living cells. ShK and its analogs are currently undergoing further evaluation as leads in the development of new biopharmaceuticals for the treatment of multiple sclerosis and other T-cell mediated autoimmune disorders.