Referenced in: none

Automatically associated channels: Kv1.3

Title: Potassium channels in T lymphocytes: therapeutic targets for autoimmune disorders?

Authors: Rosane Vianna-Jorge, Guilherme Suarez-Kurtz

Journal, date & volume: , 2004 , 18, 329-41

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/15377175

Abstract
Human peripheral blood T lymphocytes possess two types of K(+) channels: the voltage-gated Kv1.3 and the calcium-activated IKCa1 channels. The use of peptidyl inhibitors of Kv1.3 and IKCa1 indicated that these channels are involved in the maintenance of membrane potential and that they play a crucial role in Ca(2+) signaling during T-cell activation. Thus, in vitro blockade of Kv1.3 and IKCa1 leads to inhibition of cytokine production and lymphocyte proliferation. These observations prompted several groups of investigators in academia and pharmaceutical companies to characterize the expression of Kv1.3 and IKCa1 in different subsets of human T lymphocytes and to evaluate their potential as novel targets for immunosuppression. Recent in vivo studies showed that chronically activated T lymphocytes involved in the pathogenesis of multiple sclerosis present unusually high expression of Kv1.3 channels and that the treatment with selective Kv1.3 inhibitors can either prevent or ameliorate the symptoms of the disease. In this model of multiple sclerosis, blockade of IKCa1 channels had no effect alone, but improved the response to Kv1.3 inhibitors. In addition, the expression of Kv1.3 and IKCa1 channels in human cells is very restricted, which makes them attractive targets for a more cell-specific and less harmful action than what is typically obtained with classical immunosuppressants. Studies using high-throughput toxin displacement, (86)Rb-efflux screening or membrane potential assays led to the identification of non-peptidyl small molecules with high affinity for Kv1.3 or IKCa1 channels. Analysis of structure-function relationships in Kv1.3 and IKCa1 channels helped define the binding sites for channel blockers, allowing the design of a new generation of small molecules with selectivity for either Kv1.3 or IKCa1, which could help the development of new drugs for safer treatment of auto-immune diseases.