Degranulation mediated killing mechanism by NK cells is dependent on store-operated Ca²⁺ entry (SOCE) and has optimum at moderate intracellular Ca²⁺ elevations so that partial block of SOCE optimizes the killing process. In this study, we tested the effect of the selective blocker of KCa3.1 channel NS6180 on SOCE and the killing efficiency of NK cells from healthy donors and NK-92 cells against T-ALL cell line Jurkat. Patch-clamp analysis showed that only one-quarter of resting NK cells functionally express KCa3.1 current, which increases 3-fold after activation by interleukins 15 and 2. Nevertheless, blockage of KCa3.1 significantly reduced SOCE and intracellular Ca²⁺ rise induced by IL-15 or target cell recognition. NS6180 (1 μM) decreased NK degranulation at zero time of coculture with Jurkat cells but already after 1 h, the degranulation reached the same level as in the control. Monitoring of target cell death by flow cytometry and confocal microscopy demonstrated that NS6180 significantly improved the killing ability of NK cells after 1 h in coculture with Jurkat cells and increased the Jurkat cell fraction with apoptotic and necrotic markers. Our data evidence a strong dependence of SOCE on KCa3.1 activity in NK cells and that KCa3.1 specific block can improve NK cytotoxicity.

01 Sep 2022·Clinical Immunology

Retroviral glycoprotein-mediated immune suppression via the potassium channel KCa3.1 – A new strategy for amelioration of inflammatory bowel diseases

Article

Author: Graversen, Jonas Heilskov ; Laska, Magdalena J ; Strøbæk, Dorte ; Blomster, Linda ; Bahrami, Shervin ; Christophersen, Palle ; Moeller, Jesper Bonnet

Peptides derived from retroviral envelope proteins have been shown to possess a wide range of immunosuppressive and anti-inflammatory activities. We have previously reported identification of such a peptide derived from the envelope protein coded by a human endogenous retrovirus (HERV). In this study, we identify that in vitro the peptide inhibits the K_Ca3.1 potassium channel, a potential target for therapy of immune diseases. We describe in vitro ENV59-GP3 effects with respect to potency of inhibition on K_Ca3.1 channels and calcium influx. Furthermore, we asses in vivo the effect of blocking K_Ca3.1 with ENV59-GP3 peptide or K_Ca3.1-blocker NS6180 on protection against DSS-induced acute colitis. ENV59-GP3 peptide treatment showed reduction of the disease score in the DSS-induced acute colitis mice model, which was comparable to effects of the K_Ca3.1 channel blocker NS6180. Analysis of cytokine production from DSS-mice model treated animals revealed equipotent inhibitory effects of the ENV59-GP3 and NS6180 compounds on the production of IL-6, TNF-α, IL-1β. These findings altogether suggest that ENV59-GP3 functions as a K_Ca3.1 channel inhibitor and underline the implications of using virus derived channel blockers for treatment of autoimmune diseases. Additionally, they open the possibilities whether K_Ca3.1 inhibition is efficacious in patients with inflammatory bowel diseases.

10 May 2018·Current NeuropharmacologyQ2 · MEDICINE

KCa3.1 Channel Modulators as Potential Therapeutic Compounds for Glioblastoma

Q2 · MEDICINE

Article

Author: Brown, Brandon M. ; Wulff, Heike ; Pressley, Brandon

BACKGROUNDThe intermediate-conductance Ca2+-activated K+ channel KCa3.1 is widely expressed in cells of the immune system such as T- and B-lymphocytes, mast cells, macrophages and microglia, but also found in dedifferentiated vascular smooth muscle cells, fibroblasts and many cancer cells including pancreatic, prostate, leukemia and glioblastoma. In all these cell types KCa3.1 plays an important role in cellular activation, migration and proliferation by regulating membrane potential and Ca2+ signaling.METHODS AND RESULTSKCa3.1 therefore constitutes an attractive therapeutic target for diseases involving excessive proliferation or activation of one more of these cell types and researchers both in academia and in the pharmaceutical industry have developed several potent and selective small molecule inhibitors of KCa3.1. This article will briefly review the available compounds (TRAM-34, senicapoc, NS6180), their binding sites and mechanisms of action, and then discuss the potential usefulness of these compounds for the treatment of brain tumors based on their brain penetration and their efficacy in reducing microglia activation in animal models of ischemic stroke and Alzheimer's disease.CONCLUSIONSenicapoc, which has previously been in Phase III clinical trials, would be available for repurposing, and could be used to quickly translate findings made with other KCa3.1 blocking tool compounds into clinical trials.

100 Deals associated with AN-726

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Indication	Highest Phase	Country/Location	Organization	Date
Inflammation	Phase 1	DK	Saniona AB	-
Inflammation	Phase 1	DK	Clevexel Pharma SAS	-
Inflammatory Bowel Diseases	Preclinical	DK	NTG Nordic Transport Group A/S	20 Dec 2012
Inflammatory Bowel Diseases	Preclinical	US	Concord Biosciences LLC	20 Dec 2012
Nervous System Diseases	Preclinical	DK	Saniona AB	-

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