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Potassium Channels in T Lymphocytes

Therapeutic Targets for Autoimmune Disorders?

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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 Ca2+ 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, 86Rb-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.

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Acknowledgments

The authors wish to thank Drs Adriana Bonomo, Maria Luísa Garcia and Gregory J. Kaczorowski for critical reading of the manuscript.

The authors declare that no conflict of interest exists. No sources of funding were used to assist in the preparation of this manuscript.

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  1. Divisão de Farmacologia, Coordenação de Pesquisa, Instituto Nacional de Câncer, Rua André Cavalcanti, 37, Rio de Janeiro, RJ, Brazil

    Rosane Vianna-Jorge & Guilherme Suarez-Kurtz

  2. Departamento de Farmacologia Básica e Clínica, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

    Rosane Vianna-Jorge

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  1. Rosane Vianna-Jorge
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  2. Guilherme Suarez-Kurtz
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Correspondence to Rosane Vianna-Jorge.

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Vianna-Jorge, R., Suarez-Kurtz, G. Potassium Channels in T Lymphocytes. BioDrugs 18, 329–341 (2004). https://doi.org/10.2165/00063030-200418050-00005

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