Abstract
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.
Copyright © 2012 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CD11b Antigen / metabolism
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CD4-Positive T-Lymphocytes / drug effects
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CD8-Positive T-Lymphocytes / drug effects
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Cell Proliferation / drug effects
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Cytokines / metabolism
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Encephalomyelitis, Autoimmune, Experimental / drug therapy*
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Encephalomyelitis, Autoimmune, Experimental / etiology
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Encephalomyelitis, Autoimmune, Experimental / genetics
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Encephalomyelitis, Autoimmune, Experimental / pathology
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Flow Cytometry
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Membrane Potentials / drug effects
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Membrane Potentials / genetics
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Myelin-Oligodendrocyte Glycoprotein / toxicity
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Nerve Tissue Proteins / antagonists & inhibitors*
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Nerve Tissue Proteins / deficiency
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Peptide Fragments / toxicity
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Potassium Channel Blockers / chemistry
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Potassium Channel Blockers / therapeutic use*
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Potassium Channels / deficiency
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Potassium Channels, Tandem Pore Domain / antagonists & inhibitors*
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Potassium Channels, Tandem Pore Domain / deficiency
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Sulfonamides / pharmacology
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Sulfonamides / therapeutic use
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Time Factors
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ortho-Aminobenzoates / pharmacology
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ortho-Aminobenzoates / therapeutic use
Substances
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2-(butane-1-sulfonylamino)-N-(1-(6-methoxypyridin-3-yl)propyl)benzamide
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CD11b Antigen
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Cytokines
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Myelin-Oligodendrocyte Glycoprotein
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Nerve Tissue Proteins
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Peptide Fragments
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Potassium Channel Blockers
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Potassium Channels
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Potassium Channels, Tandem Pore Domain
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Sulfonamides
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TASK3 protein, mouse
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myelin oligodendrocyte glycoprotein (34-56)
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ortho-Aminobenzoates
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potassium channel subfamily K member 3