As research into ion channels continues to identify novel targets for multiple and diverse diseases, therapeutic successes surrounding the development of channel modulators will boom (for a full overview of this area, Click here to access Ion Channels as Therapeutic Targets for Multiple Diseases). Numerous companies are engaged in R&D programs involving ion channels in a number of areas, including asthma, inflammation, arrhythmia and CNS disorders, and drugs targeting ion channels already generate over $6 billion in sales per annum. Despite their remarkable physiological value, ion channels have remained a relatively unexploited therapeutic target, especially in comparison to G-protein coupled receptors or kinases. This situation is rapidly changing with the appearance of improved screening tools as well as highly targeted libraries of candidate channel modulators (see for example the Potassium channel enterprise library recently featured by LeadDiscovery).

One channel that is receiving growing interest in the scientific community is the voltage-gated K + channel, Kv1.3. This channel is one of two potassium channels expressed by human T lymphocytes that are involved in proliferation and cytokine secretion (the other is the calcium-activated K + channel IKCa1). Researchers at the University of California have recently reported that myelin-reactive encephalitogenic rat T cells expressed unusually high numbers of Kv1.3 channels following antigenic stimulation. Furthermore adoptive transfer of these T cells induced multiple sclerosis-like inflammation in rats, an effect which was reduced by Kv1.3 blockade. The search for Kv1.3 blockers or molecules able to prevent channel expression could therefore provide novel anti-inflammatory molecules.

Indeed Merck researchers have recently published a series of Kv1.3 channel inhibitors for the potential treatment of autoimmune diseases. Blockade of the channel led to diminution of T cell activation and delayed type hypersensitivity. Previous in vitro studies of the blockade were focused on T cell activation and proliferation. More recently, Kashmira Shah and colleagues from Merck examined other T and monocytic cell mediated events to determine the extent of the immunosuppressive effects of a Kv1.3 specific inhibitor, Margatoxin (MgTX). They found that MgTX inhibited the intracellular production of Th-1 as well as Th-2 cytokines. MgTX can also inhibit IL-2 production and proliferation of T cells upon stimulation with anti-CD3 and VCAM-1. Furthermore, MgTX also inhibited a redirected cytolytic activity. However, MgTX did not inhibit generation of CTL to EBV transformed lymphoma cells or antibody-dependent cellular cytolysis mediated by monocytes. It appears therefore that Kv1.3 blockade does not affect all immune responses, particularly those of innate immunity. These important finding suggest that Kv1.3 blockers may be used to treat autoimmune disorders such as multiple sclerosis and rheumatoid arthritis without seriously compromising host defenses against infection.

Entry date Thursday, June 05, 2003
Adapted from Shah et al, Cell Immunol 2003 Feb;221(2):100-6

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