Kv1.3 potassium channels as a therapeutic target in multiple sclerosis

Abstract

We discuss the potential use of inhibitors of Kv1.3 potassium channels in T lymphocytes as therapeutics for multiple sclerosis. Current treatment strategies target the immune system in a non-selective manner. The resulting general immunosuppression, toxic side-effects and increased risk of opportunistic infections create the need for more selective therapeutics. Autoreactive effector-memory T (T_EM) cells, considered to be major mediators of autoimmunity, express large numbers of Kv1.3 channels. Selective blockers of Kv1.3 inhibit calcium signaling, cytokine production and proliferation of T_EM cells in vitro, and T_EM cell-motility in vivo. Kv1.3 blockers ameliorate disease in animal models of multiple sclerosis, rheumatoid arthritis, type 1 diabetes mellitus and contact dermatitis without compromising the protective immune response to acute infections. Kv1.3 blockers have a good safety profile in rodents and primates.

Keywords::

• autoimmune disease
• effector-memory T cell
• Kv1.3 channel
• multiple sclerosis
• potassium channel

Acknowledgements

We would like to thank Prof. Daniele Piomelli (University of California Irvine) for providing us with Anandamide for patch-clamp experiments. We thank Shawn Iadonato (Kineta, Inc., Seattle) for providing us with Cynomolgus monkey peripheral blood mononuclear cells under the aegis of approved IACUC protocols SNBL-USA (A4261-01) or Washington National Primate Research Center (A3464-01) from healthy animals.