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Upregulation of K 2P 5.1 potassium channels in multiple sclerosis
Author(s) -
Bittner Stefan,
Bobak Nicole,
Herrmann Alexander M.,
Göbel Kerstin,
Meuth Patrick,
Höhn Karin G.,
Stenner MaxPhilipp,
Budde Thomas,
Wiendl Heinz,
Meuth Sven G.
Publication year - 2010
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.22010
Subject(s) - downregulation and upregulation , gene knockdown , multiple sclerosis , cd8 , potassium channel , cerebrospinal fluid , t cell , immune system , small interfering rna , chemistry , cell , medicine , cancer research , microbiology and biotechnology , endocrinology , biology , immunology , transfection , gene , biochemistry
Objective Activation of T cells critically depends on potassium channels. We here characterize the impact of K 2P 5.1 (KCNK5; TASK2), a member of the 2‐pore domain family of potassium channels, on T‐cell function and demonstrate its putative relevance in a T‐cell–mediated autoimmune disorder, multiple sclerosis (MS). Methods Expression of K 2P 5.1 was investigated on RNA and protein level in different immune cells and in MS patients' biospecimens (peripheral blood mononuclear cells, cerebrospinal fluid cells, brain tissue specimen). Functional consequences of K 2P 5.1 expression were analyzed using pharmacological modulation, small interfering RNA (siRNA), overexpression, electrophysiological recordings, and computer modeling. Results Human T cells constitutively express K 2P 5.1. After T‐cell activation, a significant and time‐dependent upregulation of K 2P 5.1 channel expression was observed. Pharmacological blockade of K 2P 5.1 or knockdown with siRNA resulted in reduced T‐cell functions, whereas overexpression of K 2P 5.1 had the opposite effect. Electrophysiological recordings of T cells clearly dissected K 2P 5.1‐mediated effects from other potassium channels. The pathophysiological relevance of these findings was demonstrated by a significant K 2P 5.1 upregulation in CD4 + and CD8 + T cells in relapsing/remitting MS (RRMS) patients during acute relapses as well as higher levels on CD8 + T cells of clinically isolated syndrome, RRMS, and secondary progressive multiple sclerosis patients during clinically stable disease. T cells in the cerebrospinal fluid from MS patients exhibit significantly elevated K 2P 5.1 levels. Furthermore, K 2P 5.1‐positive T cells can be found in inflammatory lesions in MS tissue specimens. Interpretation Selective targeting of K 2P 5.1 may hold therapeutic promise for MS and putatively other T‐cell–mediated disorders. ANN NEUROL 2010;68:58–69