Monday, 12 June 2017

Blocking potassium channels in immune cells to inhibit experimental disease.

Huang J, Han S, Sun Q, Zhao Y, Liu J, Yuan X, Mao W, Peng B, Liu W, Yin J, He X. Kv1.3 channel blocker (ImKTx88) maintains blood-brain barrier in experimental autoimmune encephalomyelitis.
Cell Biosci. 2017 Jun 7;7:31.

BACKGROUND:Disruption of blood-brain barrier (BBB) and subsequent infiltration of auto-reactive T lymphocytes are major characteristics of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). Kv1.3 channel blockers are demonstrated potential therapeutic effects on MS patients and EAE models, maybe via reducing activation of T cells. However, it remains to be explored whether Kv1.3 channel blockers maintain integrity of BBB in MS model.
RESULTS:In this study, ImKTx88, a highly selective Kv1.3 channel blocker, was used to determine the role of Kv1.3 channel in the pathogenesis of EAE, particularly in the maintenance of BBB. ImKTx88 ameliorated pathological severity in the EAE rats, and reduced extravasation into CNS. ImKTx88 also ameliorated the severity of loss or redistribution of tight junction proteins, and inhibited over-expression of ICAM-1 and VCAM-1 in the brain from EAE rats. Furthermore ImKTx88 protection was associated with activation of Ang-1/Tie-2 axis, and might be due to decreased IL-17 production.
CONCLUSIONS: ImKTx88 may be a novel therapeutic agent for MS treatment by stabilizing the BBB.

We have been talking about potasssium recently, so here is another study in EAE and this time a blocker of KV1.3 also known as KNCA3. Potassium channel, voltage-gated, shaker-related subfamily. This member contains six membrane-spanning domains with a shaker-type repeat in the fourth segment. It belongs to the delayed rectifier class, members of which allow nerve cells to efficiently repolarize following an action potential. don't worry I don't understand this either..but it is not important

KCNA3 encodes the voltage-gated Kv1.3 channel, which is expressed in T and B lymphocytes. All human T cells express roughly 300 Kv1.3 channels per cell along with 10-20 calcium-activated KCa3.1 channels. Upon activation, naive and central memory T cells increase expression of the KCa3.1 channel to approximately 500 channels per cell, while effector-memory T cells increase expression of the Kv1.3 channel. Among human B cells, naive and early memory B cells express small numbers of Kv1.3 and KCa3.1 channels when they are quiescent, and augment KCa3.1 expression after activation.In contrast, class-switched memory B cells express high numbers of Kv1.3 channels per cell (about 1500/cell) and this number increases after activation. So in humans would this be a useful approach to block KNCA3. Maybe, bt what would the effect of blocked in KCNA3 on nerves be. Calcium entry through the CRAC channel is promoted by potassium efflux through the Kv1.3 and KCa3.1 potassium channelsBlockade of Kv1.3 channels in effector-memory T cells suppresses calcium signaling, cytokine production (interferon-gamma, interleukin 2) and cell proliferation.

This probably says it all. In this study they show no markers of pathology in the blood vessel, but as endothelial cells do not have much KCNA3 the effects are probably not on the blood brain bariier but secondary to T cells being blocked in the periphery somewhere. So they never arrive in the CNS, so no upregulation of ICAM, VCAM and no effect on tight junctions as cells are not being recruited. We have said this is how many other agents work, if I used fingolimod to treat EAE and then looked for ICAM, VCAM and tight junction proteins we would see the same thing.



2 comments:

  1. Is this why lamotrigine causes initial brain shrinkage?

    ReplyDelete

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