Ion channels and lymphocyte activation
ABSTRACT The ion channels expressed by T lymphocytes play key roles in the control of the membrane potential and calcium signaling, thereby affecting signal transduction pathways that lead to the activation of these cells following antigenic stimulation. Disruption of these pathways can attenuate or prevent the response of T-cells to antigenic challenge resulting in immune suppression. Studies using ion channel blockers of high affinity and specificity have shown that this interference can be achieved at the level of ion channels. Suppression of immune functions by channel blockers has been demonstrated in vitro and in vivo. New information about the molecular structure of ion channels facilitates the design of more potent and more specific inhibitors. Thus, T-cell ion channels are likely to serve as targets for immunomodulatory drugs in the near future. Here, the biophysical properties, tissue distribution, regulation of expression, molecular pharmacology and role in T-cell activation of the voltage-gated Kv1.3 and the Ca(2+)-activated IKCa1 potassium channels and those of the Ca(+) release-activated Ca(2+) (CRAC) channel are reviewed.
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- "SKCa channels are also expressed in hematopoietic cells, where they modulate reactive oxygen species by neutrophils.55 In lymphocytes, several types of potassium channels (especially Kv1.3 and IKCa1) were reported with particular roles in mitogen- and antigen-specific proliferation, cell volume regulation, and apoptosis.56,57 "
ABSTRACT: Adenosine is a nucleoside displaying various biological effects via stimulation of four G-protein-coupled receptors, A1, A2A, A2B, and A3. Adenosine also modulates voltage-gated (Kv) and small conductance calcium-activated (SKCa) potassium channels. The effect of these potassium channels on the expression of adenosine receptors is poorly understood. We evaluated the action of BgK (a natural Kv channel blocker) and Lei-Dab7 (a synthetic SKCa channel blocker) on the expression of adenosine A2A receptors (A2AR) in Jurkat human T cells. We found that Lei-Dab7, but not BgK, increased the maximal binding value of the tritiated ligand ZM241385 to A2AR in a dose-dependent manner (+45% at 5 nM; +70% at 50 nM as compared to control). These results were further confirmed by Western blotting using a specific monoclonal antibody to human A2AR. The ligand affinity-related dissociation constant and A2AR mRNA amount were not significantly modified by either drug. We suggest that modulation of SKCa channels can influence membrane expression of A2AR and thus has a therapeutic potential.04/2013; 2(2):163-168. DOI:10.1089/biores.2012.0282
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- "The sustained influx of extracellular Ca 2+ in coordination with Ca 2+ released from the intracellular stores triggers Ca 2+ -calmodulin-dependent phosphatase calcineurin. The consequent activation of the transcription factor NFAT is thought to be the critical signaling responsible for T cell activation (Panyi et al., 2004). As such, blocking plasma membrane Kv1.3 by extracellularly applied toxins has been shown to inhibit T cell activation in an experimental autoimmune encephalomyelitis model of multiple sclerosis, rheumatoid arthritis and type-1 diabetes (Beeton et al., 2001; 2006). "
ABSTRACT: Sigma1 receptors (Sigma1R) are intracellular chaperone proteins that bind psychotropic drugs and also clinically used drugs such as ketamine and haloperidol. Co-expression of the Sigma1R has been reported to enhance the sensitivity of several voltage-gated ion channels to Sigma1R ligands. Kv1.3 is the predominant voltage-gated potassium channel expressed in T lymphocytes with a documented role in immune activation. To gain a better understanding of Sigma1R modulation of Kv ion channels, we investigated the effects of Sigma1R co-expression on Kv1.3 physiology and pharmacology in ion channels expressed in Xenopus oocytes. We also explored the protein domains of Kv1.3 necessary for protein:protein interaction between Kv1.3 and Sigma1R through co-immunoprecipitation studies. Slowly inactivating outward-going currents consistent with Kv1.3 expression were elicited on step depolarizations. The current characterized by E(rev), V(1/2), and slope factor remained unchanged when co-expressed with Sigma1R. Analysis of inactivation time constant revealed a faster Kv1.3 current decay when co-expressed with Sigma1R. However the sensitivity to Sigma1R ligands remained unaltered when co-expressed with the Sigma1R in contrast to the previously reported modulation of ligand sensitivity in closely related Kv1.4 and Kv1.5 voltage gated potassium channels. Co-immunoprecipitation assays of various Kv1.3 truncation constructs indicated that the transmembrane domain of the Kv1.3 protein was responsible for the protein:protein interaction with the Sigma1R. Sigma1R likely interacts with different domains of Kv ion channel family proteins resulting in distinct modulation of different channels.Brain research 03/2012; 1452:1-9. DOI:10.1016/j.brainres.2012.02.070 · 2.83 Impact Factor
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- "This model is similar to how Hodgkin and Huxley modeled ion currents across neuronal membranes, and has been well established in studying the electrical properties of neurons (Hodgkin and Huxley, 1952). In the human T cell, however, a few modifications to the neuronal model need to be made to include the three dominant membrane currents; the Ca 2+ current through CRAC and the K + current through Kv1.3 and KCa3.1 (Cahalan and Chandy, 2009; Panyi et al., 2004a). The membrane potential of the T cell using this equivalent circuit can be defined as, (1) where C M is the capacitance of the cell membrane, V M is the cell membrane potential, I CRAC is current through CRAC channels, I Kv1.3 is current through Kv1.3 channels, and I KCa3.1 is current through KCa3.1 channels. "
ABSTRACT: The response of T cells to antigens (T cell activation) is marked by an increase in intracellular Ca²⁺ levels. Voltage-gated and Ca²⁺-dependent K⁺ channels control the membrane potential of human T cells and regulate Ca²⁺ influx. This regulation is dependent on proper accumulation of K⁺ channels at the immunological synapse (IS) a signaling zone that forms between a T cell and antigen presenting cell. It is believed that the IS provides a site for regulation of the activation response and that K⁺ channel inhibition occurs at the IS, but the underlying mechanisms are unknown. A mathematical model was developed to test whether K⁺ efflux through K⁺ channels leads to an accumulation of K⁺ in the IS cleft, ultimately reducing K⁺ channel function and intracellular Ca²⁺ concentration ([Ca²⁺](i)). Simulations were conducted in models of resting and activated T cell subsets, which express different levels of K⁺ channels, by varying the K⁺ diffusion constant and the spatial localization of K⁺ channels at the IS. K⁺ accumulation in the IS cleft was calculated to increase K⁺ concentration ([K⁺]) from its normal value of 5.0 mM to 5.2-10.0 mM. Including K⁺ accumulation in the model of the IS reduced calculated K⁺ current by 1-12% and consequently, reduced calculated [Ca²⁺](i) by 1-28%. Significant reductions in K⁺ current and [Ca²⁺](i) only occurred in activated T cell simulations when most K⁺ channels were centrally clustered at the IS. The results presented show that the localization of K⁺ channels at the IS can produce a rise in [K⁺] in the IS cleft and lead to a substantial decrease in K⁺ currents and [Ca²⁺](i) in activated T cells thus providing a feedback inhibitory mechanism during T cell activation.Journal of Theoretical Biology 01/2012; 300:173-82. DOI:10.1016/j.jtbi.2012.01.018 · 2.30 Impact Factor