ArticleACS chemical biology2013
A high-throughput functional screen identifies small molecule regulators of temperature- and mechano-sensitive K2P channels.
Article in ACS chemical biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed, 99 citations in OpenAlex.
- KArchiv der Pharmazie · 2026Review
- Insights into the structure and modulation of human TWIK-2.Nature communications · 2026Article
- K2P channels as emerging therapeutic targets for pain: insights from functional studies and transcriptomic analyses.Frontiers in pharmacology · 2026Review
- Targeting TMEM175 in Lysosomal Physiology and Human Diseases.Current stem cell research & therapy · 2026Review
- TREK- 1 Ameliorates Secondary Brain Injury by Regulating Inflammatory Microenvironment via CX3 CL1-CX3 CR1 Pathway After Intracerebral Hemorrhage.Molecular neurobiology · 2025Article
- TREK-1 and epilepsy: regulating the balance of KBehavioral and brain functions : BBF · 2025Review
- Article
- Discovery of ONO-2920632 (VU6011887): A Highly Selective and CNS Penetrant TREK-2 (TWIK-Related K+ Channel 2) Preferring ActivatorACS chemical neuroscience · 2025Article
- Potassium channel TASK-5 forms functional heterodimers with TASK-1 and TASK-3 to break its silence.Nature communications · 2024Article
- Development of covalent chemogenetic KCell chemical biology · 2024Article
- Development of covalent chemogenetic KbioRxiv : the preprint server for biology · 2023Article
- A photoswitchable inhibitor of TREK channels controls pain in wild-type intact freely moving animals.Nature communications · 2023Article
- Effect of mechanical forces on cellular response to radiation.Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology · 2022Review
- Parkinson's disease-risk protein TMEM175 is a proton-activated proton channel in lysosomes.Cell · 2022Article
- Development of Non-opioid Analgesics Targeting Two-pore Domain Potassium Channels.Current neuropharmacology · 2022Review
- Two-Pore-Domain Potassium (KCells · 2021Review
- TREK channel activation suppresses migraine pain phenotype.iScience · 2021Article
- Structural Insights into the Mechanisms and Pharmacology of KJournal of molecular biology · 2021Review
- A "Target Class" Screen to Identify Activators of Two-Pore Domain Potassium (K2P) Channels.SLAS discovery : advancing life sciences R & D · 2021Article
- Convergence of Multiple Stimuli to a Single Gate in TREK1 and TRAAK Potassium Channels.Frontiers in pharmacology · 2021Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
K2P (KCNK) potassium channels generate "leak" potassium currents that strongly influence cellular excitability and contribute to pain, somatosensation, anesthesia, and mood. Despite their physiological importance, K2Ps lack specific pharmacology. Addressing this issue has been complicated by the challenges that the leak nature of K2P currents poses for electrophysiology-based high-throughput screening strategies. Here, we present a yeast-based high-throughput screening assay that avoids this problem. Using a simple growth-based functional readout, we screened a library of 106,281 small molecules and identified two new inhibitors and three new activators of the mammalian K2P channel K2P2.1 (KCNK2, TREK-1). By combining biophysical, structure-activity, and mechanistic analysis, we developed a dihydroacridine analogue, ML67-33, that acts as a low micromolar, selective activator of temperature- and mechano-sensitive K2P channels. Biophysical studies show that ML67-33 reversibly increases channel currents by activating the extracellular selectivity filter-based C-type gate that forms the core gating apparatus on which a variety of diverse modulatory inputs converge. The new K2P modulators presented here, together with the yeast-based assay, should enable both mechanistic and physiological studies of K2P activity and facilitate the discovery and development of other K2P small molecule modulators.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.