Upregulation of K2P5.1 potassium channels in multiple sclerosis.

Abstract

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.

• Authors: Stefan Bittner, Nicole Bobak, Alexander M Herrmann, Kerstin Göbel, Patrick Meuth, Karin G Höhn, Max-Philipp Stenner, Thomas Budde, Heinz Wiendl, Sven G Meuth
• Journal: Annals of neurology (Ann Neurol) Vol. 68 Issue 1 Pg. 58-69 (Jul 2010) ISSN: 1531-8249 [Electronic] United States
• PMID: 20582984 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CD3 Complex
• KCNK5 protein, human
• Potassium Channel Blockers
• Potassium Channels, Tandem Pore Domain
• RNA, Messenger

Topics

• Brain (metabolism)
• CD3 Complex (metabolism)
• CD4-Positive T-Lymphocytes (drug effects, physiology)
• CD8-Positive T-Lymphocytes (drug effects, physiology)
• Cell Line
• Cerebrospinal Fluid
• Humans
• Leukocytes, Mononuclear (metabolism)
• Membrane Potentials (drug effects, physiology)
• Multiple Sclerosis (physiopathology)
• Potassium Channel Blockers (pharmacology)
• Potassium Channels, Tandem Pore Domain (antagonists & inhibitors, genetics, metabolism)
• RNA, Messenger (metabolism)
• T-Lymphocytes (drug effects, physiology)
• Up-Regulation