(17,18) K V1.3 is up-regulated in activated effector memory T cells (T EM cells), a subset enriched among pathogenic autoreactive T cells in many autoimmune diseases. (10−16) The channel performs similar functions in B lymphocytes. (8,9) K V1.3 is part of a signalosome in the plasma membrane that clusters at the immunological synapse and serves to couple external stimuli with intracellular signaling cascades that are essential for cellular homeostasis and activation in T cells. (6,7) The functional channel in lymphocytes is a tetramer of K V1.3 subunits complexed to a tetramer of K Vβ2 accessory subunits. (2−5) The KCNA3 gene encoding the K V1.3 channel was identified in 1990. (1) Ion channels entered the immunological realm in 1984 when human T lymphocytes, quintessential nonelectrically excitable cells, were found to express voltage-dependent potassium (K V) currents that were required for T cell proliferation. Their role in nonexcitable cells was less appreciated until patch-clamp analysis made it possible to record electrical signals from single cells. Ion channels underlie electrical activity of excitable cells in the nervous system, heart, and muscle. EgK5 shows promise for clinical development as a therapeutic for autoimmune diseases. No signs of toxicity are observed at 10–100 times the in vivo dose. It was also effective in treating disease in a rat model of atopic dermatitis. In keeping with its arthrotropism, EgK5 treats disease in a rat model of rheumatoid arthritis. PET-CT imaging with 18F-labeled EgK5 shows accumulation of the peptide in large and small joints of rodents. EgK5 suppresses antigen-triggered proliferation of effector memory T cells, a subset enriched among pathogenic autoreactive T cells in autoimmune disease. ![]() ![]() EgK5 exhibits selectivity for K V1.3 over other channels, receptors, transporters, and enzymes. EgK5 enters plasma membranes and binds to K V1.3, causing current run-down by a phosphatidylinositol 4,5-bisphosphate-dependent mechanism. We describe a cysteine-rich, membrane-penetrating, joint-targeting, and remarkably stable peptide, EgK5, that modulates voltage-gated K V1.3 potassium channels in T lymphocytes by a distinctive mechanism.
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