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Last update 08 May 2025

KCNK6

Last update 08 May 2025

Basic Info

Synonyms

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

+ [8]

Introduction

K(+) channel that conducts outward rectifying currents at the membranes of the endolysosomal system (PubMed:10887187, PubMed:28381826). Active in lysosomes where it regulates lysosome numbers and size (PubMed:28381826). In macrophages, enables K(+) efflux coupled to ATP-induced NLRP3 inflammasome activation upon bacterial infection. Cooperates with ATP-gated P2RX7 channels to activate NLRP3 inflammasome, with P2RX7 conducting Ca(2+) and Na(+) influx that sets the membrane potential for K(+) efflux (By similarity). Does not display channel activity.

Drugs associated with KCNK6

NPBA-4

Target

KCNK6

Mechanism

KCNK6 inhibitors

Active Org.

Southern Medical University

Originator Org.

Southern Medical University

Active Indication

Inflammation

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with KCNK6

100 Translational Medicine associated with KCNK6

0 Patents (Medical) associated with KCNK6

Literatures (Medical) associated with KCNK6

01 Apr 2025·Immunology Letters

X-ray irradiation reduces ATP-dependent activation of NLRP3 inflammasome by inhibiting TWIK2 activity in macrophages

Article

Author: Song, Renjie ; Sun, Tianjing ; Niu, Man ; Duan, Haizhen ; Yu, Anyong ; Zhang, Tianxi ; Zhang, Ji ; Xie, Fangke ; Jiang, Xuheng ; Huang, Xiaofei ; Li, Mo

BACKGROUNDThe spleen, as the body's largest peripheral immune organ and a crucial source of circulating monocytes, plays a significant role in the acute inflammatory response of spleen-derived macrophages to diseases. Therefore, studying the impact and mechanism of X-ray irradiation on spleen-derived macrophages' inflammatory responses is of great importance.METHODExtracted and identified mice splenic macrophages were divided into four groups: control group, LPS and ATP co-stimulated non-irradiated group, LPS and ATP co-stimulated group irradiated after 6 h, and LPS and ATP co-stimulated group irradiated after 12 h In the LPS and ATP co-stimulated groups, LPS (1μg/ml) and ATP (5mmol/L) were added to establish an inflammatory model in mice splenic macrophages. The irradiated groups were exposed to a medical linear accelerator (Elekta Synergy), while the non-irradiated groups were placed under the light source for the same duration without irradiation. Protein extraction was performed in each group at 6 h and 12 h post-treatment for subsequent analysis using Western blot, ELISA, RT-qPCR and other relevant methods.RESULTS(1) Compared with the non-irradiated group, the cell activity in the groups irradiated for 6 h and 12 h at 8 Gy showed a significant increase (P<0.01). (2) In the LPS and ATP co-stimulated groups irradiated after 6 h and 12 h, the expression of NLRP3 mRNA and protein, IL-18 and IL-1β showed a notable decrease compared to the LPS and ATP co-stimulated non-irradiated group (P<0.05). Additionally, caspase-1 expression of caspase-1 mRNA and protein in the 12 h post-irradiation group also decreased considerably when compared with the LPS and ATP co-stimulated non-irradiated group (P < 0.05). In the groups irradiated after 6 h and 12 h, (3) there was a remarkable decrease in the expression of TWIK mRNA and TWIK2, (4) as well as Gq mRNA and protein, when compared to the LPS and ATP co-stimulated non-irradiated group (P < 0.05). Particularly, the 12 h post-irradiation group exhibited a notable reduction in PKC expression (P < 0.05).CONCLUSIONX-ray irradiation is capable of inhibiting the activation of ATP-dependent NLRP3 inflammasomes in splenic macrophages.

05 Mar 2025·ACS Chemical Neuroscience

Discovery of ONO-2920632 (VU6011887): A Highly Selective and CNS Penetrant TREK-2 (TWIK-Related K+ Channel 2) Preferring Activator In Vivo Tool Compound

Article

Author: Mori, Takahiro ; Sekioka, Yoko ; Lindsley, Craig W. ; Denton, Jerod S. ; Boutaud, Olivier ; Kurata, Haruto ; Yashiro, Kentaro ; Engers, Darren W. ; Isami, Koichi ; McGowan, Kevin M. ; Kokubo, Masaya ; Bridges, Thomas M. ; Kato, Junya ; Iwaki, Yuzo ; Wieting, Joshua ; Urata, Hirohito

Herein we describe our initial work on the K₂P family of potassium ion channels with the chemical optimization and characterization of a novel series of TWIK-Related K+ Channel (TREK)-1/2 dual activators and TREK-2 preferring activators derived from a high-throughput screening hit. The exercise provided TREK activators with good CNS penetration and others with low CNS exposure to enable exploration of both central and peripheral TREK activation. From this, ONO-2920632 (VU6011887 = 19b) emerged as a reasonably potent (human Tl⁺; TREK-1 EC₅₀ = 2.8 μM (95% E_max), TREK-2 EC₅₀ = 0.30 μM (184% E_max)), first-generation CNS penetrant (rat K_p = 0.37) in vivo tool compound with selectivity versus the other K₂P channels (>91-fold selective vs TASK1, TASK2, TASK3, TRAAK, TWIK2, and 31-fold selective vs TRESK) and no significant activity in a large ancillary pharmacology panel. ONO-2920632 (VU6011887) displayed robust, dose dependent efficacy when dosed orally in a mouse pain model (acetic acid writhing assay), where it was equipotent at 3 mg/kg to the assay standard indomethacin at 10 mg/kg. The therapeutic potential of TREK channel activation has long been hampered by a lack of selective, small molecule tools, and this work provides a variety of in vivo tool compounds for the community.

02 Jan 2025·International Reviews of Immunology

The m6A methyltransferase METTL3 modifies Kcnk6 promoting on inflammation associated carcinogenesis is essential for colon homeostasis and defense system through histone lactylation dependent YTHDF2 binding

Article

Author: Xie, Haitang ; Zhao, Jun ; Wang, Qiong ; Yuan, Xiaolong ; Pu, Zhichen

Inflammation induces tumor formation and plays a crucial role in tumor progression and prognosis. KCNK6, by regulating K(+) efflux to reduce NLRP3 Inflammasome-induced lung injury, relaxes the aorta. This study aims to elucidate the effects and biological mechanism of KCNK6 in inflammation-associated carcinogenesis, which may be essential for colon homeostasis and the defense system. To induce colitis, mice were given 3.0% Dextran Sodium Sulfate (DSS) in their drinking water for 7 days. The Azoxymethane (AOM) +DSS method was used to induce colon cancer in the mice model. Bone marrow-derived macrophages (BMDM) from Kcnk6-/- mice, AW264.7 cells, and human colon cancer HCT116 and Caco2 cells were used as in vitro models. The loss of Kcnk6 prevented spontaneous colitis and restored mucosal integrity and homeostatic molecules. Additionally, the loss of Kcnk6 reduced the severity of AOM/DSS-induced carcinogenesis. Kcnk6 promoted cell viability and proliferation in HCT-116 or Caco-2 cells. The loss of Kcnk6 inhibited the levels of inflammatory factors in BMDM cells. Kcnk6 accelerated potassium channel activity, inducing NLRP3 inflammasome activation. METTL3-mediated m6A modification increased Kcnk6 stability in a YTHDF2-dependent manner. Histone lactylation activated the transcription of YTHDF2/Kcnk6. Our study revealed the important role of Kcnk6 in inflammation-associated carcinogenesis progression. The m6A methyltransferase METTL3 and histone lactylation increased Kcnk6 stability in a YTHDF2-dependent manner, providing a potential strategy for inflammation-associated carcinogenesis or colorectal cancer therapy.

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