ArticleThe Journal of general physiology2021
Norfluoxetine inhibits TREK-2 K2P channels by multiple mechanisms including state-independent effects on the selectivity filter gate.
Article in The Journal of general physiology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 35 citations in OpenAlex.
- One pocket to activate them all (?): Efforts on understanding the modulator pocket in K2P channels.Channels (Austin, Tex.) · 2026Review
- Structural determinants for GPCR-mediated inhibition of TASK K2P channels by diacylglycerol and its dysfunction in disease.The EMBO journal · 2026Article
- From Selective Permeation to Physiology in Potassium Channels.Function (Oxford, England) · 2025Review
- Cryo-EM structure of the human THIK-1 K2P KNature structural & molecular biology · 2025Article
- Unraveling the Molecular Reason of Opposing Effects of α-Mangostin and Norfluoxetine on TREK-2 at the Same Binding Site.ChemMedChem · 2024Article
- Effect of two activators on the gating of a KBiophysical journal · 2024Article
- Atomistic mechanism of coupling between cytosolic sensor domain and selectivity filter in TREK K2P channels.Nature communications · 2024Article
- Extracellular modulation of TREK-2 activity with nanobodies provides insight into the mechanisms of K2P channel regulation.Nature communications · 2024Article
- Potassium Leak Channels and Mitochondrial Complex I Interact in Glutamatergic Interneurons of the Mouse Spinal Cord.Anesthesiology · 2024Article
- Research progress of two-pore potassium channel in myocardial ischemia-reperfusion injury.Frontiers in physiology · 2024Review
- Cloxyquin activates hTRESK by allosteric modulation of the selectivity filter.Communications biology · 2023Article
- TREK-1 and TREK-2 Knockout Mice Are Not Resistant to Halothane or Isoflurane.Anesthesiology · 2023Article
- Membrane phospholipids control gating of the mechanosensitive potassium leak channel TREK1.Nature communications · 2023Article
- Multiple Effects of Echinochrome A on Selected Ion Channels Implicated in Skin Physiology.Marine drugs · 2023Article
- Transition between conformational states of the TREK-1 K2P channel promoted by interaction with PIPBiophysical journal · 2022Article
- Structural Basis for pH-gating of the KNature communications · 2022Article
- Muscimol Directly Activates the TREK-2 Channel Expressed in GABAergic Neurons through Its N-Terminus.International journal of molecular sciences · 2021Article
- Negative Influence by the Force: Mechanically Induced Hyperpolarization via KInternational journal of molecular sciences · 2021Review
- Convergence of Multiple Stimuli to a Single Gate in TREK1 and TRAAK Potassium Channels.Frontiers in pharmacology · 2021Article
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
Abstract
The TREK subfamily of two-pore domain K+ (K2P) channels are inhibited by fluoxetine and its metabolite, norfluoxetine (NFx). Although not the principal targets of this antidepressant, TREK channel inhibition by NFx has provided important insights into the conformational changes associated with channel gating and highlighted the role of the selectivity filter in this process. However, despite the availability of TREK-2 crystal structures with NFx bound, the precise mechanisms underlying NFx inhibition remain elusive. NFx has previously been proposed to be a state-dependent inhibitor, but its binding site suggests many possible ways in which this positively charged drug might inhibit channel activity. Here we show that NFx exerts multiple effects on single-channel behavior that influence both the open and closed states of the channel and that the channel can become highly activated by 2-APB while remaining in the down conformation. We also show that the inhibitory effects of NFx are unrelated to its positive charge but can be influenced by agonists which alter filter stability, such as ML335, as well as by an intrinsic voltage-dependent gating process within the filter. NFx therefore not only inhibits channel activity by altering the equilibrium between up and down conformations but also can directly influence filter gating. These results provide further insight into the complex allosteric mechanisms that modulate filter gating in TREK K2P channels and highlight the different ways in which filter gating can be regulated to permit polymodal regulation.
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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.