K+ channels as targets for specific immunomodulation

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Abstract

The voltage-gated Kv1.3 channel and the Ca2+-activated IKCa1 K+ channel are expressed in T cells in a distinct pattern that depends on the state of lymphocyte activation and differentiation. The channel phenotype changes during the progression from the resting to the activated cell state and from naı̈ve to effector memory cells, affording promise for specific immunomodulatory actions of K+ channel blockers. In this article, we review the functional roles of these channels in both naı̈ve cells and memory cells, describe the development of selective inhibitors of Kv1.3 and IKCa1 channels, and provide a rationale for the potential therapeutic use of these inhibitors in immunological disorders.

Section snippets

Molecular interactions at the immunological synapse

The T-cell-mediated immune response is initiated by recognition of processed antigenic peptide bound to major histocompatibility complex (MHC) proteins on antigen-presenting cells (APCs) by the antigen-specific multi-subunit T-cell receptor (TCR)–CD3 complex on T cells (Figure 2). Within minutes the TCR–CD3 complex and accessory proteins cluster at the zone of contact with the APC in a region termed the ‘immunological synapse’ (IS). Antigen-induced redistribution of key receptors and signaling

Pharmacology of Kv1.3 and IKCa1 channels

The roles of Kv1.3 and IKCa1 channels have been defined in T cells with the help of structurally diverse peptides, small molecules and metal ions that block these channels with potencies ranging from picomolar to millimolar values. Figure 3, Figure 4 display the chemical structures of selected peptide and small organic inhibitors, whereas Table 1, Table 2 provide lists of Kv1.3 and IKCa1 channel modulators in order of decreasing potency. For Kv1.3, but not IKCa1, channels the potency of peptide

K+ channels in T cells: targets for immunomodulation

The immunomodulatory effects of channel blockers depend on the expression levels of Kv1.3 and IKCa1 channels, which change dramatically when T cells transition from resting to activated cells, and during differentiation from the naı̈ve to the memory state 15, 40, 56. Figure 5a shows the three human T-cell subsets that are distinguished based on the expression of the chemokine receptor CCR7 and the phosphatase CD45RA [57]: naı̈ve cells (CCR7+CD45RA+); central memory cells (TCM) (CCR7+CD45RA);

Concluding remarks

Much work remains to be done to bring IKCa1 and Kv1.3 channel blockers to the clinic. The situation with small-molecule IKCa1 channel blockers is encouraging because ICA17043 is already in Phase II clinical trials for sickle cell disease and TRAM34 has been used successfully in an in vivo animal trial [54]. Both these agents and the newly described 4-phenyl-4H-pyran need to be evaluated in animal models of organ graft rejection, acute active EAE and rheumatoid arthritis.

Existing small-molecule

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