ReviewIon channels and lymphocyte activation
Introduction
Clonal expansion of lymphocytes, in vivo, is required to generate an efficient generalized immune response to a specific antigen. Binding of peptide-loaded MHC to the T-cell receptor–CD3 complex (TCR/CD3) results in the recruitment and activation of protein tyrosine kinases, such as members of Src, Zap-70/Syk, Tec and Csk families of non-receptor tyrosine kinases, and the concomitant activation of phospholipase C-γ (PLCγ). PLCγ cleaves phosphatidylinositol 4,5-bisphosphate into diacylglycerol and 1,4,5-inositol trisphosphate (IP3), and in turn, initiates two signaling pathways in lymphocyte activation. Diacylglycerol activates the protein kinase C (PKC) pathway, particularly through protein kinase Cθ, which leads to the phosphorylation of several intracellular substrates and the triggering of transcription via the assembly of the Fos/Jun transcription factor complex on AP1 elements in several genes. The second pathway, initiated by the generation of IP3, governs the sustained elevation of the cytosolic free Ca2+ concentration ([Ca2+]i) required for efficient signal transduction. The calcium signal activates the Ca2+-calmodulin-dependent phospahatase calcineurin. Calcineurin then dephosphorylates the transcription factor NF-AT thereby enabling it to accumulate in the nucleus and bind to the promoter element of the interleukin-2 (IL-2) gene. Activation of IL-2 gene and IL-2 expression is a critical commitment point beyond which further T-cell activation becomes antigen independent. A sustained Ca2+ signal is required to keep NF-AT in the nucleus in the transcriptionally active state.
The sustained Ca2+ signal relies on the operation of the ion channels in T-cells, especially the voltage-gated Kv1.3 and the Ca2+-activated IKCa1 potassium channels and the Ca2+ release-activated Ca2+ (CRAC) channel. In this paper we review the role of these ion channels in T-cell activation in addition to their biophysical properties, tissue distribution, regulation, pharmacology and their connection to certain diseases.
Section snippets
Intracellular and plasma membrane Ca2+ channels participating in the generation of the Ca2+ signal
Two sequentially coupled mechanisms contribute to the generation of the Ca2+ signal in T-cells. The first event is the binding of IP3 to the IP3-receptor (IP3R) located in the membrane of the endoplasmic reticulum. IP3R engagement with its ligand results in the release of Ca2+ stored in the lumen of the ER causing a rise in the [Ca2+]i from a resting level of ∼100 nM to a peak concentration of ∼500 nM (reviewed in [1]).
In addition to the extensively studied IP3–IP3R system, a cyclic ADP-ribose
Membrane potential dependence of the Ca2+ signal, the role of potassium channels
An interesting, physiologically important feature of the CRAC channel is its membrane potential-independent gating and its inward rectification [5]. This means that once the CRAC channels are activated the electrochemical driving force for Ca2+ will determine the magnitude of the inward current. The driving force increases with membrane hyperpolarization, which, along with the inward rectification of the current, results in larger Ca2+ current at negative membrane potentials. This unusual
Tissue distribution of Kv1.3 and IKCa1 channels, regulation of their expression
The tissue distribution of Kv1.3 channels is relatively restricted to the immune system and the central nervous system. In the immune system very interesting changes in K+ channel expression accompany the proliferation, maturation and differentiation of T-cells. Subset specific expression of ion channels in murine thymocytes was described relatively early [59]. Immature CD4+CD8+ cells express ∼300 Kv1.3 channels; the expression level of this channel drops dramatically (∼20 channel per cell) upon
Production of high affinity and high specificity blockers of Kv1.3 and IKCa1 channels: potential immunosuppressors
Soon after the characterization of Kv1.3 channels and Ca2+-activated K+ channels in lymphocytes it was discovered that channel-blocking agents are able to inhibit T-cell activation, including secretion of lymphokines, cell proliferation, and killing of target cells in vitro as well as in vivo (see above). These initial observations led to the search for high specificity and high affinity blockers of Kv1.3 and IKCa1 channels (reviewed recently in [52], [74], [75]). Research in this field was
New perspective: regulation of Kv1.3 channels by supramolecular clusters important in T-cell signaling
Interaction of T lymphocytes with professional antigen presenting cells is required for in vivo activation of T-cells. This interaction takes place at a specialized intercellular contact, called immunological synapse (IS), where the encounter causes proteins to segregate into micrometer-scale domains [86]. Formation of the IS between T-cells and antigen presenting cells recruits LFA-1 in the periphery and TCR/CD3, CD28 and CD2 membrane proteins in the center of the supramolecular activation
Concluding remarks
Critical information accumulated in the past two decades about the biophysical and pharmacological properties of Kv1.3 and IKCa1 channels. The function of these channels in regulating the membrane potential and Ca2+ signaling is well supported. Discovery of potent and selective blockers of Kv1.3 and IKCa1 along with the characterization of subset specific expression of these channels led to successful and selective suppression of lymphocyte activation in vitro and most importantly, in vivo as
Acknowledgements
This work was supported by grants from the following agencies: OTKA TS040773, T043087, F035251, ETT 222/2003, 010/2001. The authors would like to thank János Matkó (Eötvös Loránd University, Budapest) for helpful discussions and critical reading of the manuscript.
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