K+ Channel Blockers: Novel Tools to Inhibit T Cell Activation Leading to Specific Immunosuppression

Abstract

During the last two decades since the identification and characterization of T cell potassium channels great advances have been made in the understanding of the role of these channels in T cell functions, especially in antigen-induced activation. Their limited tissue distribution and the recent discovery that different T cell subtypes carrying out distinct immune functions show specific expression levels of these channels have made T cell potassium channels attractive targets for immunomodulatory drugs. Many toxins of various animal species and a structurally diverse array of small molecules inhibiting these channels with varying affinity and selectivity were found and their successful use in immunosuppression in vivo was also demonstrated. Better understanding of the topological differences between potassium channel pores, detailed knowledge of toxin and small-molecule structures and the identification of the binding sites of blocking compounds make it possible to improve the selectivity and affinity of the lead compounds by introducing modifications based on structural information. In this review the basic properties and physiological roles of the voltage-gated Kv1.3 and the Ca2+-activated IKCa1 potassium channels are discussed along with an overview of compounds inhibiting these channels and approaches aiming at producing more efficient modulators of immune functions for the treatment of diseases like sclerosis multiplex and type I diabetes.

Variability of Potassium Channel Blockers in Mesobuthus eupeus Scorpion Venom with Focus on Kv1.1

“…Importantly, some of the toxins display remarkable selectivity with respect to different potassium channel isoforms (11)(12)(13)(14)(15), a property that justifies their potential as drug leads (16). Alternatively, high selectivity may be achieved by means of chemical modification and targeted or random mutagenesis of natural peptide molecules (17)(18)(19)(20).…”

Structure of the full-length Shaker potassium channel Kv1.2 by normal-mode-based X-ray crystallographic refinement

“…Among them, voltage-dependent potassium channels (Kv) have been most extensively studied (2)(3)(4)(5)(6). In an action potential, the Kv channel allows intracellular potassium getting out of the cell to return the membrane potential to the polarized state, the failure of which could cause overexcitability of neuron cells, leading to neuronal diseases (7,8). The Kv channel is a homotetramer with four voltage sensors and one central pore domain (9,10).…”

Ion channels and anti-cancer immunity

“…Non-peptide, small-molecule inhibitors of Kv1.3 were identified with very diverse chemical structures [9]. Some of these molecules were also developed on a natural template, e.g.…”