Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0014070 (encephalomyelitis)
 13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two major K(+) channels are expressed in T cells, (i) the voltage-dependent K(V)1.3 channel and (ii) the Ca(2+)-activated K(+) channel KCa 3.1 (IKCa channel). Both critically influence T cell effector functions in vitro and animal models in vivo. Here we identify and characterize TWIK-related acid-sensitive potassium channel 1 (TASK1) and TASK3 as an important third K(+) conductance on T lymphocytes. T lymphocytes constitutively express TASK1 and -3 protein. Application of semi-selective TASK blockers resulted in a significant reduction of cytokine production and cell proliferation. Interference with TASK channels on CD3(+) T cells revealed a dose-dependent reduction ( approximately 40%) of an outward current in patch clamp recordings indicative of TASK channels, a finding confirmed by computational modeling. In vivo relevance of our findings was addressed in an experimental model of multiple sclerosis, adoptive transfer experimental autoimmune encephalomyelitis. Pretreatment of myelin basic protein-specific encephalitogenic T lymphocytes with TASK modulators was associated with significant amelioration of the disease course in Lewis rats. These data introduce K(2)P channels as novel potassium conductance on T lymphocytes critically influencing T cell effector function and identify a possible molecular target for immunomodulation in T cell-mediated autoimmune disorders.
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PMID:TWIK-related acid-sensitive K+ channel 1 (TASK1) and TASK3 critically influence T lymphocyte effector functions. 1837 52

Multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) are characterized by T cell-mediated autoimmune inflammation of the central nervous system (CNS) leading to oligodendrocyte loss and demyelination accompanied by neuronal cell death. Neuronal TWIK-related acid-sensitive potassium (TASK) channels allow the regulated efflux of potassium ions. These channels might either protect neurons in the inflamed CNS by modulating electrical excitability or even contribute to inflammatory neurodegeneration mediating intracellular potassium depletion. Using a combination of in-situ-hybridisation and immunofluorescence staining, we found increased neuronal expression of TASK1 and TASK3 channels in the optic nerve and decreased expression in the spinal cord and thalamus of rats undergoing MOG-induced EAE. Inflammatory plaques of human MS patients displayed profoundly lowered expression of both TASK isoforms. Thus, regulated expression of TASK channels might contribute to a molecular switch between death and survival of neurons in autoimmune CNS inflammation.
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PMID:Altered neuronal expression of TASK1 and TASK3 potassium channels in rodent and human autoimmune CNS inflammation. 1882 70

We provide evidence that TWIK-related acid-sensitive potassium channel 1 (TASK1), a member of the family of two-pore domain potassium channels relevant for setting the resting membrane potential and balancing neuronal excitability that is expressed on T cells and neurons, is a key modulator of T cell immunity and neurodegeneration in autoimmune central nervous system inflammation. After induction of experimental autoimmune encephalomyelitis, an experimental model mimicking multiple sclerosis, TASK1(-/-) mice showed a significantly reduced clinical severity and markedly reduced axonal degeneration compared with wild-type controls. T cells from TASK1(-/-) mice displayed impaired T cell proliferation and cytokine production, while the immune repertoire is otherwise normal. In addition to these effects on systemic T cell responses, TASK1 exhibits an independent neuroprotective effect which was demonstrated using both a model of acutely prepared brain slices cocultured with activated T cells as well as in vitro cultivation experiments with isolated optic nerves. Anandamide, an endogenous cannabinoid and inhibitor of TASK channels, reduced outward currents and inhibited effector functions of T cells (IFN-gamma production and proliferation); an effect completely abrogated in TASK1(-/-) mice. Accordingly, preventive blockade of TASK1 significantly ameliorated experimental autoimmune encephalomyelitis after immunization. Therapeutic application of anandamide significantly reduced disease severity and was capable of lowering progressive loss of brain parenchymal volume as assessed by magnetic resonance imaging. These data support the identification and characterization of TASK1 as potential molecular target for the therapy of inflammatory and degenerative central nervous system disorders.
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PMID:TASK1 modulates inflammation and neurodegeneration in autoimmune inflammation of the central nervous system. 1957 Aug 51

The two-pore domain potassium channel TASK1 (KCNK3) has recently emerged as an important modulator in autoimmune CNS inflammation. Previously, it was shown that T lymphocytes obtained from TASK1(-/-) mice display impaired T cell effector functions and that TASK1(-/-) mice show a significantly reduced disease severity in myelin oligodendrocyte glycoprotein (MOG(35-55)) peptide induced experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. We here evaluate a potent and specific TASK1 channel inhibitor, A293, which caused a dose-dependent reduction of T cell effector functions (cytokine production and proliferation). This effect was abolished in CD4(+) T cells from TASK1(-/-) mice but not in cells from TASK3(-/-) mice. In electrophysiological measurements, A293 application induced a significant reduction of the outward current of wildtype T lymphocytes, while there was no effect in TASK1(-/-) cells. Preventive and therapeutic application of A293 significantly ameliorated the EAE disease course in wildtype mice while it had no significant effect in TASK1(-/-) mice and was still partly effective in TASK3(-/-) mice. In summary, our findings support the concept of TASK1 as an attractive drug target for autoimmune disorders.
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PMID:The TASK1 channel inhibitor A293 shows efficacy in a mouse model of multiple sclerosis. 2296 Jan 85

Two-pore domain potassium channels, such as TASK, are essential players in the regulation of the resting membrane potential. A recent publication in Experimental Neurology revealed that the pharmacological blockade of the two-pore domain potassium channel TASK1 improved clinical disease severity, the number of cellular infiltrates, as well as the degree of demyelination in experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis. This effect was driven by a reduction in the generation of proinflammatory cytokines and proliferation of T lymphocytes. Thus, functional activity of T lymphocytes was identified to be TASK1 dependent suggesting that this class of potassium channels may represent an interesting target for treating T cell-driven autoimmunity directed against the central nervous system.
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PMID:Targeting two-pore domain potassium channels - a promising strategy for treating T cell mediated autoimmunity. 2335 39