更新于：2024-11-01

KCNK6

更新于：2024-11-01

基本信息

别名

Inward rectifying potassium channel protein TWIK-2、K2p6.1、KCNK6

+ [8]

简介

Exhibits outward rectification in a physiological K(+) gradient and mild inward rectification in symmetrical K(+) conditions.

关联

项与 KCNK6 相关的药物

NPBA-4

靶点

KCNK6

作用机制

KCNK6抑制剂

在研机构

南方医科大学

原研机构

南方医科大学

在研适应症

炎症

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 KCNK6 相关的临床结果

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100 项与 KCNK6 相关的转化医学

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0 项与 KCNK6 相关的专利（医药）

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项与 KCNK6 相关的文献（医药）

2024-07-01·Inflammation Research

Extracellular histones promote TWIK2-dependent potassium efflux and associated NLRP3 activation in alveolar macrophages during sepsis-induced lung injury

Article

作者: Zhang, Zhiyuan ; Chen, Chang ; Yu, Jing ; Wen, Zongmei ; Jiang, Xuemei ; Gao, Jiameng ; Zhang, Nan ; Fu, Yu

BACKGROUND AND AIMSepsis-induced acute lung injury (ALI) is a complex and life-threatening condition lacking specific and efficient clinical treatments. Extracellular histones, identified as a novel type of damage-associated molecular patterns, have been implicated in the inflammatory process of ALI. However, further elucidation is needed regarding the precise mechanism through which extracellular histones induce inflammation. The aim of this study was to investigate whether extracellular histones can activate NLRP3 inflammasome-mediated inflammation in alveolar macrophages (AMs) by affecting TWIK2-dependent potassium efflux.METHODS AND RESULTSWe conducted experiments using cecal ligation and puncture (CLP) C57BL/6 mice and extracellular histone-stimulated LPS-primed MH-S cells. The results demonstrated a significant increase in the levels of extracellular histones in the plasma and bronchoalveolar lavage fluid (BALF) of CLP mice. Furthermore, neutralizing extracellular histone mitigated lung injury and inflammation in CLP-induced ALI mice. In vitro studies confirmed that extracellular histones upregulated the expression of NLRP3 inflammasome activation-related proteins in MH-S cells, and this effect was dependent on increased potassium efflux mediated by the TWIK2 channel on the plasma membrane. Moreover, extracellular histones directly triggered a substantial influx of calcium, leading to increased Rab11 activity and facilitating the trafficking and location of TWIK2 to the plasma membrane.CONCLUSIONThese findings underscore the critical role of extracellular histone-induced upregulation of TWIK2 expression on the plasma membrane of alveolar macrophages (AMs). This upregulation leads to potassium efflux and subsequent activation of the NLRP3 inflammasome, ultimately exacerbating lung inflammation and injury during sepsis.

2024-04-01·Chemico-Biological Interactions

Transcriptomic and proteomic study of cancer cell lines exposed to actinomycin D and nutlin-3a reveals numerous, novel candidates for p53-regulated genes

Article

作者: Gdowicz-Kłosok, Agnieszka ; Krześniak, Małgorzata ; Łasut-Szyszka, Barbara ; Będzińska, Agnieszka ; Pietrowska, Monika ; Gawin, Marta ; Małachowska, Beata ; Rusin, Marek

Transcriptomic analyses have revealed hundreds of p53-regulated genes; however, these studies used a limited number of cell lines and p53-activating agents. Therefore, we searched for candidate p53-target genes by employing stress factors and cell lines never before used in a high-throughput search for p53-regulated genes. We performed RNA-Seq on A549 cells exposed to camptothecin, actinomycin D, nutlin-3a, as well as a combination of actinomycin D and nutlin-3a (A + N). The latter two substances synergise upon the activation of selected p53-target genes. A similar analysis was performed on other cell lines (U-2 OS, NCI-H460, A375) exposed to A + N. To identify proteins in cell lysates or those secreted into a medium of A549 cells in control conditions or treated with A + N, we employed mass spectrometry. The expression of selected genes strongly upregulated by A + N or camptothecin was examined by RT-PCR in p53-deficient cells and their controls. We found that p53 participates in the upregulation of: ACP5, APOL3, CDH3, CIBAR2, CRABP2, CTHRC1, CTSH, FAM13C, FBXO2, FRMD8, FRZB, GAST, ICOSLG, KANK3, KCNK6, KLRG2, MAFB, MR1, NDRG4, PTAFR, RETSAT, TMEM52, TNFRSF14, TRANK1, TYSND1, WFDC2, WFDC5, WNT4 genes. Twelve of these proteins were detected in the secretome and/or proteome of treated cells. Our data generated new hypotheses concerning the functioning of p53. Many genes activated by A + N or camptothecin are also activated by interferons, indicating a noticeable overlap between transcriptional programs of p53 and these antiviral cytokines. Moreover, several identified genes code for antagonists of WNT/β-catenin signalling pathways, which suggests new connections between these two cancer-related signalling systems. One of these antagonists is DRAXIN. Previously, we found that its gene is activated by p53. In this study, using mass spectrometry and Western blotting, we detected expression of DRAXIN in a medium of A549 cells exposed to A + N. Thus, this protein functions not only in the development of the nervous system, but it may also have a new cancer-related function.

2023-12-01·Biochemical Pharmacology

A novel TWIK2 channel inhibitor binds at the bottom of the selectivity filter and protects against LPS-induced experimental endotoxemia in vivo

Article

作者: Wu, Xiaoyan ; Chen, Xingyuan ; Chen, Xiangyu ; Cao, Ying ; Chen, Yao ; Chen, Yanshan ; Li, Fengxian ; Lin, Xiuling ; Ma, Liang ; Zhi, Yuanxing ; Yi, Xin ; Zhou, Pingzheng ; Luo, Hui

TWIK2 channel plays a critical role in NLRP3 inflammasome activation and mice deficient in TWIK2 channel are protected from sepsis and inflammatory lung injury. However, inhibitors of TWIK2 channel are currently in an early stage of development, and the molecular determinants underlying the chemical modulation of TWIK2 channel remain unexplored. In this study, we identified NPBA and the synthesized derivative NPBA-4 potently and selectively inhibited TWIK2 channel by using whole-cell patch clamp techniques. Furthermore, the mutation of the last residues of the selectivity filter in both P1 and P2 (i.e., T106A, T214A) of TWIK2 channel substantially abolished the effect of NPBA on TWIK2 channel. Our data suggest that NPBA blocked TWIK2 channel through binding at the bottom of the selectivity filter, which was also supported by molecular docking prediction. Moreover, we found that NPBA significantly suppressed NLRP3 inflammasome activation in macrophages and alleviated LPS-induced endotoxemia and organ injury in vivo. Notably, the protective effects of NPBA against LPS-induced endotoxemia were abolished in Kcnk6^-/- mice. In summary, our study has uncovered a series of novel inhibitors of TWIK2 channel and revealed their distinct molecular determinants interacting TWIK2 channel. These findings provide new insights into the mechanisms of pharmacological action on TWIK2 channel and opportunities for the development of selective TWIK2 channel modulators to treat related inflammatory diseases.