KCNK17

Last update 08 May 2025

Basic Info

Synonyms

2P domain potassium channel Talk-2, Acid-sensitive potassium channel protein TASK-4, K2p17.1

+ [12]

Introduction

K(+) channel that conducts voltage-dependent outward rectifying currents upon membrane depolarization. Voltage sensing is coupled to K(+) electrochemical gradient in an 'ion flux gating' mode where outward but not inward ion flow opens the gate (PubMed:11248242, PubMed:11263999, PubMed:26919430, PubMed:36063992). Homo- and heterodimerizes to form functional channels with distinct regulatory and gating properties (PubMed:36063992). Present in the cardiac conduction system where it may regulate action potential duration and beating frequency of cardiac myocytes (PubMed:24972929). Permeable to other monovalent cations such as Rb(+) and Cs(+) (By similarity) (PubMed:26919430).

100 Clinical Results associated with KCNK17

100 Translational Medicine associated with KCNK17

0 Patents (Medical) associated with KCNK17

Literatures (Medical) associated with KCNK17

01 Apr 2025·Journal of Biological Chemistry

Rational design, synthesis, and evaluation of novel polypharmacological compounds targeting NaV1.5, KV1.5, and K2P channels for atrial fibrillation

Article

Author: Gutiérrez, Margarita ; Schütte, Sven ; Mazola, Yuliet ; González, Wendy ; Venturini, Whitney ; Rodriguez, Blanca ; Wiedmann, Felix ; Prent-Peñaloza, Luis ; Bedoya, Mauricio ; Márquez Montesinos, José C E ; Bueno-Orovio, Alfonso ; Prüser, Merten ; Dasí, Albert ; Decher, Niels ; Zúñiga, Rafael ; Kiper, Aytug K ; Varela, Diego ; Adasme-Carreño, Francisco ; Camargo-Ayala, Lorena ; Peña-Martínez, Paula A ; Camargo-Ayala, Paola Andrea ; Rinné, Susanne ; Zúñiga, Leandro ; Schmidt, Constanze ; Ravens, Ursula

Atrial fibrillation (AF) involves electrical remodeling of the atria, with ion channels such as Na_V1.5, K_V1.5, and TASK-1 playing crucial roles. This study investigates acetamide-based compounds designed as multi-target inhibitors of these ion channels to address AF. Compound 6f emerged as the most potent in the series, demonstrating a strong inhibition of TASK-1 (IC₅₀ ∼ 0.3 μM), a moderate inhibition of Na_V1.5 (IC₅₀ ∼ 21.2 μM) and a subtle inhibition of K_V1.5 (IC₅₀ ∼ 81.5 μM), alongside unexpected activation of TASK-4 (∼ 40% at 100 μM). Functional assays on human atrial cardiomyocytes from sinus rhythm (SR) and patients with AF revealed that 6f reduced action potential amplitude in SR (indicating Na_V1.5 block), while in AF it increased action potential duration (APD), reflecting high affinity for TASK-1. Additionally, 6f caused hyperpolarization of the resting membrane potential in AF cardiomyocytes, consistent with the observed TASK-4 activation. Mathematical modeling further validated its efficacy in reducing AF burden. Pharmacokinetic analyses suggest favorable absorption and low toxicity. These findings identify 6f as a promising multi-target therapeutic candidate for AF management.

01 Oct 2022·Journal of Biological Chemistry

Alkaline-sensitive two-pore domain potassium channels form functional heteromers in pancreatic β-cells

Article

Author: Feliciangeli, Sylvain ; Gilbert, Nicolas ; Abelanet, Sophie ; Chatelain, Franck C ; Kang, Dawon ; Bichet, Delphine ; Khoubza, Lamyaa ; Kim, Eun-Jin ; Lesage, Florian

Two-pore domain K⁺ channels (K_2P channels), active as dimers, produce inhibitory currents regulated by a variety of stimuli. Among them, TWIK1-related alkalinization-activated K⁺ channel 1 (TALK1), TWIK1-related alkalinization-activated K⁺ channel 2 (TALK2), and TWIK1-related acid-sensitive K⁺ channel 2 (TASK2) form a subfamily of structurally related K_2P channels stimulated by extracellular alkalosis. The human genes encoding these proteins are clustered at chromosomal region 6p21 and coexpressed in multiple tissues, including the pancreas. The question whether these channels form functional heteromers remained open. By analyzing single-cell transcriptomic data, we show that these channels are coexpressed in insulin-secreting pancreatic β-cells. Using in situ proximity ligation assay and electrophysiology, we show that they form functional heterodimers both upon heterologous expression and under native conditions in human pancreatic β-cells. We demonstrate that heteromerization of TALK2 with TALK1 or with TASK2 endows TALK2 with sensitivity to extracellular alkalosis in the physiological range. We further show that the association of TASK2 with TALK1 and TALK2 increases their unitary conductance. These results provide a new example of heteromerization in the K_2P channel family expanding the range of the potential physiological and pathophysiological roles of TALK1/TALK2/TASK2 channels, not only in insulin-secreting cells but also in the many other tissues in which they are coexpressed.

08 Aug 2022·JNCI: Journal of the National Cancer Institute

A Novel Locus on 6p21.2 for Cancer Treatment–Induced Cardiac Dysfunction Among Childhood Cancer Survivors

Article

Author: Plyler, Emily ; Qin, Na ; Sapkota, Yadav ; Burridge, Paul W ; Shelton, Kyla ; Liu, Qi ; Jefferies, John L ; Hudson, Melissa M ; Oeffinger, Kevin C ; Morton, Lindsay M ; Zhang, Jinghui ; Mulrooney, Daniel A ; Easton, John ; Armstrong, Gregory T ; Chow, Eric J ; Bhatia, Smita ; Yang, Jun J ; Li, Chunliang ; Wilson, Carmen L ; Wang, Zhaoming ; Robison, Leslie L ; Yasui, Yutaka ; Shao, Ying ; Mulder, Heather L ; Michael, J Robert ; Qiu, Weiyu ; Wang, Xuexia ; Ehrhardt, Matthew J

AbstractBackgroundAdult survivors of childhood cancer are at increased risk of cardiac late effects.MethodsUsing whole-genome sequencing data from 1870 survivors of European ancestry in the St. Jude Lifetime Cohort (SJLIFE) study, genetic variants were examined for association with ejection fraction (EF) and clinically assessed cancer therapy–induced cardiac dysfunction (CCD). Statistically significant findings were validated in 301 SJLIFE survivors of African ancestry and 4020 survivors of European ancestry from the Childhood Cancer Survivor Study. All statistical tests were 2-sided.ResultsA variant near KCNK17 showed genome-wide significant association with EF (rs2815063-A: EF reduction = 1.6%; P = 2.1 × 10-8) in SJLIFE survivors of European ancestry, which replicated in SJLIFE survivors of African ancestry (EF reduction = 1.5%; P = .004). The rs2815063-A also showed a 1.80-fold (P = .008) risk of severe or disabling or life-threatening CCD and replicated in 4020 Childhood Cancer Survivor Study survivors of European ancestry (odds ratio = 1.40; P = .04). Notably, rs2815063-A was specifically associated among survivors exposed to doxorubicin only, with a stronger effect on EF (3.3% EF reduction) and CCD (2.97-fold). Whole blood DNA methylation data in 1651 SJLIFE survivors of European ancestry showed statistically significant correlation of rs2815063-A with dysregulation of KCNK17 enhancers (false discovery rate <5%), which replicated in 263 survivors of African ancestry. Consistently, the rs2815063-A was associated with KCNK17 downregulation based on RNA sequencing of 75 survivors.ConclusionsLeveraging the 2 largest cohorts of childhood cancer survivors in North America and survivor-specific polygenomic functional data, we identified a novel risk locus for CCD, which showed specificity with doxorubicin-induced cardiac dysfunction and highlighted dysregulation of KCNK17 as the likely molecular mechanism underlying this genetic association.

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KCNK17

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