Blocking ion channel KCNN4 alleviates the symptoms of experimental autoimmune encephalomyelitis in mice

Abstract

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-a and IFN-c 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.See accompanying Commentary: http://dx

Blockade of Ca2+‐activated K+ channels in T cells: an option for the treatment of multiple sclerosis?

“…Remarkably, in the present issue of European Journal of Immunology, Reich et al [4] from the ScheringPlough Research Institute provide compelling pharmacological evidence that selective blockage of the IK channel with TRAM-34 protects mice against antigeninduced development of EAE. In contrast to the adoptive transfer of T cells, this model relies on immunization by a peptide fragment of the myelin oligodendrocyte glycoprotein ).…”

“…Blockers of both channel types have given promising results in various in vitro assays for T cell activation [1][2][3][4]8]. The gold standard for evaluation of the potential of a new molecular target is, however, to obtain effects in validated animal models such as inhibition of host-graft reactions or animal models of autoimmune diseases, such as multiple sclerosis.…”

“…Novel, low-toxicity immune suppressants are therefore warranted. Many lines of evidence indicate that compounds inhibiting specific K + channels in T cells may represent an entirely new class of immune-suppressants that could fulfill this need [2][3][4].…”

The Ca2+-Activated K+ChannelKCNN4/KCa3.1 Contributes to Microglia Activation and Nitric Oxide-Dependent Neurodegeneration

“…Bayer (Wuppertal, Germany) developed several KCa3.1 blockers, tested them in a rat model of traumatic brain injury (subdural hematoma), and found that several hours of intravenous administration of either a triazole or a cyclohexadiene compound significantly reduced the ensuing edema, intracranial pressure, and infarct volume (Mauler et al, 2004). KCa3.1 blockade reduced inflammatory cytokine production and damage in the spinal cord in a murine model of multiple sclerosis (Reich et al, 2005), but potential contributions of CNS cells were not determined. Blocking KCa3.1 channels in endothelia and smooth muscle cells in the rat middle cerebral artery inhibited hyperpolarization and vessel relaxation (McNeish et al, 2006).…”

Role of an S4-S5 Linker Lysine in the Trafficking of the Ca2+-activated K+ Channels IK1 and SK3

“…hIK1 has also been shown to play a role in both macrophage activation and T-lymphocyte proliferation (10 -12). The critical role that pharmacological modulation of hIK1 may play has been revealed by the demonstration that blockers of hIK1 reduce the autoimmune response to experimental encephalomyelitis in mice (13), reduce brain edema following traumatic brain injury (14), and prevent restenosis following balloon angioplasty (15). Also, openers have been shown to alter vascular tone and hence may modulate peripheral blood pressure (16,17).…”