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Last update 08 May 2025

TASK-1

Last update 08 May 2025

Basic Info

Synonyms

Acid-sensitive potassium channel protein TASK-1, K2p3.1, KCNK3

+ [11]

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:23169818, PubMed:26919430, PubMed:32499642, PubMed:36195757, PubMed:9312005). Changes ion selectivity and becomes permeable to Na(+) ions in response to extracellular acidification. Protonation of the pH sensor His-98 stabilizes C-type inactivation conformation likely converting the channel from outward K(+)-conducting, to inward Na(+)-conducting to nonconductive state (PubMed:22948150). Homo- and heterodimerizes to form functional channels with distinct regulatory and gating properties (PubMed:23169818, PubMed:32499642). Allows K(+) currents with fast-gating kinetics important for the repolarization and hyperpolarization phases of action potentials (By similarity). In cerebellar granule cells, heteromeric KCNK3:KCNK9 channel may hyperpolarize the resting membrane potential to limit intrinsic neuronal excitability, but once the action potential threshold is reached, it may support high-frequency action potential firing and increased neuronal excitability (By similarity). Dispensable for central chemosensory respiration i.e. breathing controlled by brainstem CO2/pH, it rather conducts pH-sensitive currents and controls the firing rate of serotonergic raphe neurons involved in potentiation of the respiratory chemoreflex. Additionally, imparts chemosensitivity to type 1 cells in carotid bodies which respond to a decrease in arterial oxygen pressure or an increase in carbon dioxide pressure or pH to initiate adaptive changes in pulmonary ventilation (By similarity). In adrenal gland, contributes to the maintenance of a hyperpolarized resting membrane potential of aldosterone-producing cells at zona glomerulosa and limits aldosterone release as part of a regulatory mechanism that controls arterial blood pressure and electrolyte homeostasis (By similarity). In brown adipocytes, mediates K(+) efflux that counteracts norepinephrine-induced membrane depolarization, limits Ca(2+) efflux and downstream cAMP and PKA signaling, ultimately attenuating lipid oxidation and adaptive thermogenesis (By similarity).

Drugs associated with TASK-1

F3(CEAP)

Target

TASK-1

Mechanism

TASK-1 inhibitors

Active Org.

Philip Morris International, Inc.

Originator Org.

Centro de Estudios en Alimentos Procesados

Active Indication

Cough

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

ML365

Target

TASK-1

Mechanism

TASK-1 inhibitors

Active Org.

Johns Hopkins Medicine, Inc. [+2]

Originator Org.

Johns Hopkins Medicine, Inc. [+1]

Active Indication

postoperative cognitive dysfunction [+1]

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

(+)-Doxapram

Target

TASK-1 x TASK-3

Mechanism

TASK-1 inhibitors [+2]

Active Org.-

Originator Org.

Galleon Pharmaceuticals, Inc.

Active Indication-

Inactive Indication

Hypoxia

Drug Highest PhaseDiscontinued

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with TASK-1

NCT05527457

/ CompletedPhase 1IIT

Effects of BAY2586116 on Obstructive Sleep Apnoea (OSA) Severity Informed by Upper Airway Physiology and the Role of Route of Breathing

This investigator-initiated study aims to determine the effects of BAY2586116 (a novel TASK channel blocker nasal spray) on sleep apnoea severity and the potential influence of route of breathing.

Start Date31 Aug 2022

Sponsor / Collaborator

Flinders University

[+1]

NCT04872387

/ CompletedPhase 1

Randomized, Placebo-controlled, Single-blind, Dose Escalation Study to Investigate the Safety, Tolerability, and Pharmacokinetics After Single and Multiple Nasal Doses of BAY 2586116 in Japanese Healthy Male Participants

BAY2586116 is a new drug in development for the treatment of obstructive sleep apnea. This is a condition that causes breathing to repeatedly stop and start during sleep due to blocked upper airways.
This is a study to learn more how safe BAY2586116 is, how it affects the body, how it moves into, through and out of the body in healthy Japanese male participants.
The participants will be randomly chosen to receive 1 of 3 different doses of BAY2586116 or to receive a placebo. A placebo looks like a treatment but does not have any medicine in it. The participants will receive their study treatment either 1 single time or once a day for 5 days through a nasal spray.
The participants will be in the study for a total of about 12 weeks. They will stay at their study site for either 5 or 9 days, depending on which study treatment they receive. During this time, the doctors will take blood and urine samples and check the participants' health. About 6 to 8 days after the participants receive their last treatment, the researchers will check the participants' health again.
The main aim of this study is to learn more about how safe BAY2586116 is compared to the placebo. To answer this question, the researchers will count the number of participants who have medical problems that may or may not be related to the study treatment. These medical problems are also known as "adverse events" while they are in the study.

Start Date11 May 2021

Sponsor / Collaborator

Bayer AG

NCT04713826

/ CompletedPhase 2

Proof-of-concept, Multi-center, Randomized, Double-blind, Placebo-controlled, Two-way Crossover Study to Investigate the Effect Strength of BAY 2586116 on the Apnea-hypopnea-index After Repetitive Nasal Doses Compared to Placebo in 80 Valid Participants With Moderate to Severe Obstructive Sleep Apnea

Researchers are looking for a better way to treat people with obstructive sleep apnea (OSA). In people with OSA, the upper airways can narrow or close repetitively while sleeping. These breathing interruptions lead to reduction of oxygen in the blood or short arousals from sleep. Before a treatment can be approved for people to take, researchers do clinical trials to better understand its safety and how well it works.
In this trial, the researchers want to learn more about how well BAY2586116 works in a small number of participants with OSA. The trial will include about 160 men and women who have OSA and are at least 18 years old. Women can only be included in this trial if they are not able to have children naturally.
In this trial, the participants will take BAY2586116 and a placebo. A placebo looks like a treatment but does not have any medicine in it. All of the participants will take BAY2586116 through a nasal spray. They will also take the placebo as a nasal spray.
This will be a crossover trial. This means all the participants will take both trial treatments one after the other, but in a different order. The participants will take each treatment once a day for 7 days.
The researchers will use a measurement called the apnea-hypopnea-index (AHI) to measure the severity of the participants' OSA. The researchers will then compare the participants' AHI scores when they take BAY2586116 and when they take the placebo.
During study, the participants will visit their trial site 5 times. At these visits the doctors will take blood samples, do physical examinations and check the participants' heart health using an electrocardiogram (ECG). They will also ask the participants questions about how they are feeling and if they have any medical problems. At 3 of the visits, the participants will stay at the trial site overnight. At these visits, the doctors will calculate the number of times the participants stop breathing per hour of sleep. After treatment, the participants will have a final visit 7 days later so the doctors can check their health.

Start Date03 Mar 2021

Sponsor / Collaborator

Bayer AG

100 Clinical Results associated with TASK-1

100 Translational Medicine associated with TASK-1

0 Patents (Medical) associated with TASK-1

671

Literatures (Medical) associated with TASK-1

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.

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.

22 Jan 2025·Current Pharmaceutical Biotechnology

Integrative Bioinformatics and Experimental Validation Reveal the Mechanistic Action of Patchouli Alcohol in Prostate Cancer Treatment

Article

Author: Zhao, Juan ; Cai, Jian ; Zhai, Songhui

Introduction:Prostate cancer is an androgen-dependent malignancy, and the use of androgen deprivation therapies frequently results in treatment resistance, relapse, and the development of aggressive castration-resistant tumors. Patchouli alcohol, a tricyclic sesquiterpene derived from Pogostemon cablin of the Labiatae family, has demonstrated potential in modulating inflammatory responses and tumor progression. This study aimed to investigate the mechanisms through which patchouli alcohol influences inflammatory pathways associated with prostate cancer using bioinformatics and experimental validation.Methods:Differentially Expressed Genes (DEGs) were identified from the GSE46602 dataset, containing 36 prostate cancer and 14 normal prostate biopsy samples, using the GEO2R tool (adjusted P < 0.05). Functional annotation was performed using GO and KEGG databases, while PPI networks were constructed via STRING and Cytoscape. Key hub genes were identified. To validate the bioinformatics findings, qPCR and Western blotting were employed to confirm the differential expression of selected hub genes in DU145 prostate cancer cells treated with patchouli oil.Results:Bioinformatic analysis revealed 71 DEGs, including 35 upregulated and 36 downregulated genes. Thirteen hub genes were identified (DCK, APRT, ADK, KCNK9, ADSL, PKM, KCNK3, S100A10, ENTPD2, PKLR, ARHGEF38, TPK1, and AK5), which were enriched in pathways, such as MAPK, PI3K-Akt, Ras, and Rap1. Experimental validation confirmed the upregulation of DCK, APRT, KCNK9, ADSL, PKM, S100A10, ENTPD2, PKLR, ARHGEF38, and AK5, and the downregulation of ADK, KCNK3, and TPK1 at both the mRNA and protein levels.Conclusion:Patchouli alcohol appears to influence multiple hub genes associated with prostate cancer progression through its modulation of key cellular signaling and metabolic pathways. These findings support its potential role as a therapeutic agent for prostate cancer.

News (Medical) associated with TASK-1

16 Feb 2023

·www.biospace.com

GeneDx Rare Disease Data Demonstrates Utility in Drug Candidate Identification for Common Diseases Research published in Nature Genetics underscores the role of genetic insights in the drug discovery and development process

STAMFORD, Conn., Feb. 16, 2023 (GLOBE NEWSWIRE) -- GeneDx Holdings Corp. (GeneDx) (Nasdaq: WGS), a leader in delivering improved health outcomes through genomic and clinical insights, continues to demonstrate how the study of rare disease can improve understanding of the biology of common disorders. Research published in the October 2022 issue of Nature Genetics, to which GeneDx contributed data and authorship, yields insights into the role of two-pore-domain potassium channels (K2P) in rare disease and explores the role genes might play in the newly described developmental delay with sleep apnea (DDSA). Such connections better enable the exploration of pharmacological solutions to common diseases impacting wide swaths of the general population. Sleep apnea, characterized by abnormal, interrupted breathing during sleep, is a common disorder that represents a global public health burden thought to affect up to one in five people worldwide and approximately 30 million Americans. Poor sleep quality often results in decreased quality of life and increased risk of comorbidities, such as cardiovascular disease, diabetes and depression. The study describes DDSA, a newly identified condition caused by de novo gain-of function variants clustering in the X-gate motif of the TASK-1 channel encoded by KCNK3. TASK-1 is a K+ channel implicated in the control of breathing, but its link with sleep apnea remains poorly understood. Functional studies indicate that TASK channel inhibitors may be effective at inhibiting abnormal channel activity caused by these variants, illuminating the underlying biology of sleep apnea and pointing to possible therapeutic options for patients with DDSA and common sleep apnea. “These findings indicate how research into rare disease can uncover findings that are potentially applicable to much broader segments of the general population and also represent important progress for the pharmacological management of sleep apnea,” said Dr. Paul Kruszka, Chief Medical Officer of GeneDx. “Sleep apnea’s high prevalence and the imperfection of existing therapies mean there is sizeable appetite for developing new treatment approaches.” Through its robust rare disease data set, GeneDx is working to advance drug discovery and development, and accelerate research to help identify therapeutic targets for common diseases. With the deep genomic information available from GeneDx’s exome and genome testing, combined with its clinical insights, the company is able to help connect biopharmaceutical companies with patients to improve clinical trial enrollments and recruitment and improve patient outcomes by connecting them to therapies. About GeneDx (formerly Sema4) GeneDx delivers personalized and actionable health insights to inform diagnosis, direct treatment and improve drug discovery. The company is uniquely positioned to accelerate the use of genomic and large-scale clinical information to enable precision medicine as the standard of care. GeneDx is at the forefront of transforming healthcare through its industry-leading exome and genome testing and interpretation, fueled by one of the world’s largest rare disease data sets. For more information, please visit genedx.com and connect with us on LinkedIn, Facebook, and Instagram. Media contact Stephanie Kahan Press@genedx.com Investor contact Tricia Truehart Investors@genedx.com

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