Blocking ion channel KCNN4 alleviates the symptoms of experimental autoimmune encephalomyelitis in mice.
The KCNN4 potassium-ion channel has been reported to play an important role in regulating antigen-induced T cell effector functions in vitro. This study presents the first evidence that a selective KCNN4 blocker, TRAM-34, confers protection against experimental autoimmune encephalomyelitis (EAE) in the mouse model. Treatment with the KCNN4 blocker did not prevent infiltration of T cells in the spinal cord, but resulted in the reduction of both the protein and the message levels of TNF-alpha and IFN-gamma as well as the message levels of several other pro-inflammatory molecules in the spinal cord. Plasma concentrations of TRAM-34 within a 24-h period were between the in vitro IC(50) and IC(90) values for the KCNN4 channel. The effect of TRAM-34 was reversible, as indicated by the development of clinical EAE symptoms within 48 h after withdrawal of treatment. In summary, our data support the idea that KCNN4 channels play a critical role in the immune response during the development of MOG-induced EAE in C57BL/6 mice.
Reich
Eva-Pia
EP
Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.
Cui
Long
L
Yang
Lily
L
Pugliese-Sivo
Catherine
C
Golovko
Andrei
A
Petro
Mary
M
Vassileva
Galya
G
Chu
Inhou
I
Nomeir
Amin A
AA
Zhang
Li-Kang
LK
Liang
Xian
X
Kozlowski
Joseph A
JA
Narula
Satwant K
SK
Zavodny
Paul J
PJ
Chou
Chuan-Chu
CC
D000818:Animals; D002465:Cell Movement / Q000276:immunology / Q000502:physiology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000517:prevention & control; D007249:Inflammation / Q000276:immunology; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D051379:Mice; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000378:metabolism; D013116:Spinal Cord / Q000276:immunology / Q000502:physiology
D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496925:Kcnn4 protein, mouse; D024681:Potassium Channels, Calcium-Activated; D012333:RNA, Messenger