Inhibition of the K⁺channel KCa3.1 ameliorates T cell–mediated colitis

Abstract

The calcium-activated K + channel KCa3.1 plays an important role in T lymphocyte Ca 2+ signaling by helping to maintain a negative membrane potential, which provides an electrochemical gradient to drive Ca 2+ influx. To assess the role of KCa3.1 channels in lymphocyte activation in vivo, we studied T cell function in KCa3.1 −/− mice. CD4 T helper (i.e., Th0) cells isolated from KCa3.1 −/− mice lacked KCa3.1 channel activity, which resulted in decreased T cell receptor–stimulated Ca 2+ influx and IL-2 production. Although loss of KCa3.1 did not interfere with CD4 T cell differentiation, both Ca 2+ influx and cytokine production were impaired in KCa3.1 −/− Th1 and Th2 CD4 T cells, whereas T-regulatory and Th17 function were normal. We found that inhibition of KCa3.1 −/− protected mice from developing severe colitis in two mouse models of inflammatory bowel disease, which were induced by ( i ) the adoptive transfer of mouse naïve CD4 T cells into rag2 −/− recipients and ( ii ) trinitrobenzene sulfonic acid. Pharmacologic inhibitors of KCa3.1 have already been shown to be safe in humans. Thus, if these preclinical studies continue to show efficacy, it may be possible to rapidly test whether KCa3.1 inhibitors are efficacious in patients with inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis.

Tripartite motif containing protein 27 negatively regulates CD4 T cells by ubiquitinating and inhibiting the class II PI3K-C2β

“…We have previously shown that one function of the class II PI3KC2β is to generate the pool of PI3P required for activating KCa3.1 and, through this function, PI3KC2β is required for TCR stimulated Ca 2+ influx in CD4 Th0, Th1, and Th2 cells (19,40,41). Thus, understanding the mechanisms for regulating PI3KC2β in the activation of KCa3.1 affords us a unique opportunity to both uncover fundamental mechanisms for regulating class II PI3Ks, as well as to identify new signaling molecules that modulate CD4 Tcell activation.…”

“…To assess whether KCa3.1 channel activity is also increased in TRIM27 −/− Th1 and Th2 CD4 T lymphocytes, CD4 T cells isolated from spleens of TRIM27 +/+ and TRIM27 −/− mice were differentiated into Th1 and Th2 cells (40). TRIM27 −/− CD4 T cells differentiated normally into Th1 and Th2 cells, as evidenced by similar expression of T-bet and GATA3, respectively, compared with TRIM27 +/+ cells (Fig.…”

“…KCa3.1 is the predominant K + channel expressed in Th0, Th1, and Th2 CD4 T cells and is required for both Ca 2+ influx and cytokine production by these cells (40,41). To assess whether KCa3.1 channel activity is also increased in TRIM27 −/− Th1 and Th2 CD4 T lymphocytes, CD4 T cells isolated from spleens of TRIM27 +/+ and TRIM27 −/− mice were differentiated into Th1 and Th2 cells (40).…”

Bacteroides fragilis polysaccharide A is necessary and sufficient for acute activation of intestinal sensory neurons

“…The sAHP is generated by the opening of an IK Ca channel. As inhibition of an IK Ca channel or its genetic ablation ameliorates T-cell-dependent murine colitis 22 , the bacteria might have therapeutic potential as oral delivery and solubility of the IK Ca channel blocker TRAM-34 are problematic 23 . Indeed, the observation that JB-1 actually does protect against experimentally induced mouse colitis 24 supports this possibility.…”

Pharmacological gating modulation of small- and intermediate-conductance Ca2+-activated K+channels (KCa2.x and KCa3.1)

“…26,27 K Ca 3.1 is a major component of the endothelial derived hyperpolarizing (EDH) response 28,29 and important for cell proliferation and cytokine release in lymphocytes. 27,30,31 Positive Modulation of K Ca 2/K Ca 3.1 Channels…”