Ca²⁺-Activated K⁺ Channel K_Ca3.1 as a Therapeutic Target for Immune Disorders

Abstract

In lymphoid and myeloid cells, membrane hyperpolarization by the opening of K channels increases the activity of Ca release-activated Ca (CRAC) channels and transient receptor potential (TRP) Ca channels. The intermediate-conductance Ca-activated K channel K3.1 plays an important role in cell proliferation, differentiation, migration, and cytokine production in innate and adaptive immune systems. K3.1 is therefore an attractive therapeutic target for allergic, inflammatory, and autoimmune disorders. In the past several years, studies have provided new insights into 1) K3.1 pharmacology and its auxiliary regulators; 2) post-transcriptional and proteasomal regulation of K3.1; 3) K3.1 as a regulator of immune cell migration, cytokine production, and phenotypic polarization; 4) the role of K3.1 in the phosphorylation and nuclear translocation of Smad2/3; and 5) K3.1 as a therapeutic target for cancer immunotherapy. In this review, we have assembled a comprehensive overview of current research on the physiological and pathophysiological significance of K3.1 in the immune system.

Histone Deacetylases Enhance Ca2+-Activated K+ Channel KCa3.1 Expression in Murine Inflammatory CD4+ T Cells

“…IBD, including ulcerative colitis (UC) and CD, are characterized by chronic inflammation of the colon. We previously reported that the up-regulated expression of the Ca 2+ -activated K + channel K Ca 3.1 in inflammatory CD4 + T cells was involved in the pathogenesis of IBD [ 4 ]. Similarly, the expression levels of K Ca 3.1 transcripts were higher in surgical specimens and endoscopic biopsies from IBD patients [ 9 ].…”

“…Similar epigenetic modifications to K Ca 3.1 were found in the “human” T cell model, the T-cell lymphoma cell line HuT-78 (unpublished data). T cells also express the other K + channels: voltage-gated K + channel K V 1.3 and two-pore-domain K + channel K 2P 5.1 [ 1 , 2 , 3 , 4 ]. No significant changes in the expression levels of K V 1.3 and K 2P 5.1 transcripts following treatment with HDACis were detected in the CD4 + T cells of IBD model mice ( Figure S5 ).…”

“…The intermediate-conductance Ca 2+ -activated K + channel K Ca 3.1 controls Ca 2+ -dependent signaling pathways and plays crucial roles in proliferation, migration, apoptosis, and cytokine production in T cells [ 1 , 2 , 3 , 4 ]. Previous studies demonstrated the involvement of K Ca 3.1 in the pathogenesis of inflammatory bowel disease (IBD) [ 5 , 6 , 7 , 8 ].…”

Inhibition of Interleukin 10 Transcription through the SMAD2/3 Signaling Pathway by Ca2+-Activated K+Channel KCa3.1 Activation in Human T-Cell Lymphoma HuT-78 Cells

“…x (2.1-2.3), and K Ca 3.1. In lymphoid and myeloid cells, membrane hyperpolarization by K 1 channel opening (i.e., K Ca 3.1, voltage-gated K V 1.3, and two-pore domain K 2P 5.1) increased the activity of Ca 21 release-activated Ca 21 channels and transient receptor potential Ca 21 channels (Cahalan and Chandy, 2009;Feske et al, 2015;Ohya and Kito, 2018).…”

“…In CD8 1 T cells with the capacity to kill malignant cells, K 1 efflux-mediating K Ca 3.1 activation increases antitumor function by promoting interferon (IFN)-g production (Eil et al, 2016). The following positive and negative K Ca 3.1 function-modifying molecules have been identified in T cells: class II phosphoinositide 3-kinase B (PI3K-C2B), nucleoside diphosphate kinase B (NDPK-B), protein histidine phosphatase-1, phosphatidylinositol 3-phosphate myotubularin-related protein, phosphoglycerate mutase family member 5, and tripartite motif (family) 27 (Ohya and Kito, 2018). In T cells, K Ca 3.1 accumulates in the uropod, but not the leading edge, and is associated with oscillations in intracellular Ca 21 levels (Kuras et al, 2012).…”