Upregulation of K2P5.1 potassium channels in multiple sclerosis.
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.


CONCLUSIONS
Selective targeting of K(2P)5.1 may hold therapeutic promise for MS and putatively other T-cell-mediated disorders.
Bittner
Stefan
S
Department of Neurology, University of Würzburg, Würzburg, Münster, Germany.
Bobak
Nicole
N
Herrmann
Alexander M
AM
Göbel
Kerstin
K
Meuth
Patrick
P
Höhn
Karin G
KG
Stenner
Max-Philipp
MP
Budde
Thomas
T
Wiendl
Heinz
H
Meuth
Sven G
SG
D001921:Brain / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002555:Cerebrospinal Fluid; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009103:Multiple Sclerosis / Q000503:physiopathology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024683:Potassium Channels, Tandem Pore Domain / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation
D017252:CD3 Complex; C410295:KCNK5 protein, human; D026902:Potassium Channel Blockers; D024683:Potassium Channels, Tandem Pore Domain; D012333:RNA, Messenger