Ion channels and lymphocyte activation
Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary. Immunology Letters
(Impact Factor: 2.51).
04/2004; 92(1-2):55-66. DOI: 10.1016/j.imlet.2003.11.020
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.
Available from: ojs.kardiologiapolska.pl
- "Recent data from experimental animal models found that T cells are associated with hypertension and inflammation . It has been shown that potassium channels are essential for the activation of T lymphocytes and that they are involved in multiple physiological processes, such as T lymphocyte differentiation, proliferation, and activation [11, 12].]) has been reported to be critical for the production of angiotensin II (Ang II), which plays a key role in the progression of essential hypertension . Other studies have shown that the anti-inflammatory effects of angiotensin II receptor blocker (ARB) may be involved in the ability of these agents to lower blood pressure [6, 13, 14]. "
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ABSTRACT: Background and aim:
Increasing evidence indicates that chronic inflammation is a direct or indirect manifestation of hypertension. Potassium channels are thought to be critical for lymphocyte activation, which suggests that hypertension may be an inflammatory disease initiated at the ion channel level.
This study investigated changes in IL-6, IL-17 and TGF-β1 expression in the blood of Kazakh hypertensive patients in Northwest China using ELISA technology. Whole-cell patch clamp technology was used to evaluate current changes associated with Kv1.3 and KCa3.1 in peripheral blood T lymphocytes of hypertensive patients, and investigate current changes induced by telmisartan. We also investigated the effects of telmisartan on expression of Kv1.3 and KCa3.1 at mRNA and protein levels in peripheral blood T lymphocytes using RT-PCR and Western blot analysis.
Expression of IL-6, IL-17 and TGF-β1 in the blood of Kazakh hypertensive patients in Northwest China was significantly higher than in healthy controls (P<0.05). The current mediated by Kv1.3 and KCa3.1 and the corresponding expression at mRNA and protein levels in T lymphocytes were also higher in these hypertensive patients than in controls (P<0.05). Telmisartan intervention for 24h and 48h inhibited the current and expression of Kv1.3 and KCa3.1 at mRNA and protein levels (P<0.05).
These results indicated that the increase in functional Kv1.3 and KCa3.1 channels expressed in T lymphocytes of Kazakh patients with hypertension was blocked by telmisartan resulting in a reduced inflammatory response. These results provide theoretical support for the treatment of hypertension at the cellular ion channel level.
Available from: Youlet By
- "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 "
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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.
Available from: Yvonne Rosenstein
- "The activity of the K channels provides the counterbalancing cation efflux required for maintenance of the negative membrane potential during Ca 2 influx. Inhibition of Kv1.3 and KCa3.1 depolarizes the membrane potential and inhibits Ca 2 entry, leading to reduced T-cell proliferation (Panyi et al., 2004; Cahalan and Chandy, 2009). T-cell subtype-specific expression of K channels significantly influences the potency of K channel blockers to inhibit T-cell proliferation. "
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ABSTRACT: Blockade of Kv1.3 K(+) channels in T cells is a promising therapeutic approach for the treatment of autoimmune diseases such as multiple sclerosis and type 1 diabetes mellitus. Vm24 (α-KTx 23.1) is a novel 36-residue Kv1.3-specific peptide isolated from the venom of the scorpion Vaejovis mexicanus smithi. Vm24 inhibits Kv1.3 channels of human lymphocytes with high affinity (K(d) = 2.9 pM) and exhibits >1500-fold selectivity over other ion channels assayed. It inhibits the proliferation and Ca(2+) signaling of human T cells in vitro and reduces delayed-type hypersensitivity reactions in rats in vivo. Our results indicate that Vm24 has exceptional pharmacological properties that make it an excellent candidate for treatment of certain autoimmune diseases.
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