title: The TASK1 channel inhibitor A293 shows efficacy in a mouse model of multiple sclerosis.
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.
authors.affiliation: University of Münster, Department of Neurology-Inflammatory Disorders of the Nervous System and Neurooncology, Münster, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bittner
authors.forename: Marcella A
authors.initials: MA
authors.lastname: Bauer
authors.forename: Petra
authors.initials: P
authors.lastname: Ehling
authors.forename: Nicole
authors.initials: N
authors.lastname: Bobak
authors.forename: Johanna
authors.initials: J
authors.lastname: Breuer
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Herrmann
authors.forename: Melina
authors.initials: M
authors.lastname: Golfels
authors.forename: Heinz
authors.initials: H
authors.lastname: Wiendl
authors.forename: Thomas
authors.initials: T
authors.lastname: Budde
authors.forename: Sven G
authors.initials: SG
authors.lastname: Meuth
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000473:pathology; D005434:Flow Cytometry; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000633:toxicity; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency; D010446:Peptide Fragments / Q000633:toxicity; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000627:therapeutic use*; D015221:Potassium Channels / Q000172:deficiency; D024683:Potassium Channels, Tandem Pore Domain / Q000037:antagonists & inhibitors* / Q000172:deficiency; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors; D062367:ortho-Aminobenzoates / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C577579:2-(butane-1-sulfonylamino)-N-(1-(6-methoxypyridin-3-yl)propyl)benzamide; D039481:CD11b Antigen; D016207:Cytokines; D063308:Myelin-Oligodendrocyte Glycoprotein; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024683:Potassium Channels, Tandem Pore Domain; D013449:Sulfonamides; C511784:TASK3 protein, mouse; C517781:myelin oligodendrocyte glycoprotein (34-56); D062367:ortho-Aminobenzoates; C420132:potassium channel subfamily K member 3