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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ABSTRACT: The voltage-dependent Kv1.3 potassium channels mediate a variety of physiological functions in human T lymphocytes. These channels, along with their multiple regulatory components, are localized in cholesterol-enriched microdomains of plasma membrane (lipid rafts). In this study, patch-clamp technique was applied to explore the impact of the lipid-raft integrity on the Kv1.3 channel functional characteristics. T lymphoma Jurkat cells were treated for 1 h with cholesterol-binding oligosaccharide methyl-β-cyclodextrin (MβCD) in 1 or 2 mM concentration, resulting in depletion of cholesterol by 63 ± 5 or 75 ± 4%, respectively. Treatment with 2 mM MβCD did not affect the cells viability but retarded the cell proliferation. The latter treatment caused a depolarizing shift of the Kv1.3 channel activation and inactivation by 11 and 6 mV, respectively, and more than twofold decrease in the steady-state activity at depolarizing potentials. Altogether, these changes underlie the depolarization of membrane potential, recorded in a current-clamp mode. The effects of MβCD were concentration- and time-dependent and reversible. Both development and recovery of the MβCD effects were completed within 1–2 h. Therefore, cholesterol depletion causes significant alterations in the Kv1.3 channel function, whereas T cells possess a potential to reverse these changes.Pflügers Archiv - European Journal of Physiology 01/2007; 454(2):235-244. · 4.87 Impact Factor
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ABSTRACT: The immune system is vital for detecting and evading endogenous and exogenous threats to the body. Failure to regulate this homeostasis leads to autoimmunity, which is often associated with malfunctioning T cell signaling. Several medications are available to suppress over-reactive T lymphocytes, but many of the currently marketed drugs produce severe and life-threatening side-effects. Ribosomally synthesized peptides are gaining recognition from the pharmaceutical industry for their enhanced selectivity and decreased toxicity compared with small molecules; in particular, circular peptides exhibit remarkable stability and increased oral administration properties. For example, plant cyclotides effectively inhibit T lymphocyte proliferation. They are composed of a head-to-tail cyclized backbone and a cystine-knot motif, which confers them with remarkable stability, thus making them attractive pharmaceutical tools.Drug discovery today 12/2013; · 6.63 Impact Factor
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ABSTRACT: Voltage-dependent K(+) channels (Kv) are involved in a number of physiological processes, including immunomodulation, cell volume regulation, apoptosis as well as differentiation. Some Kv channels participate in the proliferation and migration of normal and tumor cells, contributing to metastasis. Altered expression of Kv1.3 and Kv1.5 channels has been found in several types of tumors and cancer cells. In general, while the expression of Kv1.3 apparently exhibits no clear pattern, Kv1.5 is induced in many of the analyzed metastatic tissues. Interestingly, evidence indicates that Kv1.5 channel shows inversed correlation with malignancy in some gliomas and non-Hodgkin's lymphomas. However, Kv1.3 and Kv1.5 are similarly remodeled in some cancers. For instance, expression of Kv1.3 and Kv1.5 correlates with a certain grade of tumorigenicity in muscle sarcomas. Differential remodeling of Kv1.3 and Kv1.5 expression in human cancers may indicate their role in tumor growth and their importance as potential tumor markers. However, despite of this increasing body of information, which considers Kv1.3 and Kv1.5 as emerging tumoral markers, further research must be performed to reach any conclusion. In this review, we summarize what it has been lately documented about Kv1.3 and Kv1.5 channels in human cancer.Frontiers in Physiology 01/2013; 4:283.