ArticleProceedings of the National Academy of Sciences of the United States of America2016
Heterodimerization within the TREK channel subfamily produces a diverse family of highly regulated potassium channels.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed, 82 citations in OpenAlex.
- One pocket to activate them all (?): Efforts on understanding the modulator pocket in K2P channels.Channels (Austin, Tex.) · 2026Review
- Role for TREK-1 as a polymodal sensor and regulator of cell activity.Channels (Austin, Tex.) · 2026Review
- Evaluation of Novel Cloxyquin Analogs for KArchiv der Pharmazie · 2026Article
- Swapped and non-swapped TRAAK states co-exist in membranes at a ratio influenced by temperature.Nature communications · 2026Article
- Thermosensitivity of TREK K2P channels is controlled by a PKA switch and depends on the microtubular network.Pflugers Archiv : European journal of physiology · 2025Article
- Structure of the human KNature structural & molecular biology · 2025Article
- An evolutionarily conserved AnkyrinG-dependent motif clusters axonal K2P K+ channels.The Journal of cell biology · 2024Article
- Potassium channel TASK-5 forms functional heterodimers with TASK-1 and TASK-3 to break its silence.Nature communications · 2024Article
- Tick-Derived Peptide Blocks Potassium Channel TREK-1.International journal of molecular sciences · 2024Article
- An ankyrin G-binding motif mediates TRAAK periodic localization at axon initial segments of hippocampal pyramidal neurons.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Development of covalent chemogenetic KCell chemical biology · 2024Article
- Structure of the human KbioRxiv : the preprint server for biology · 2024Article
- Extracellular modulation of TREK-2 activity with nanobodies provides insight into the mechanisms of K2P channel regulation.Nature communications · 2024Article
- Research progress of two-pore potassium channel in myocardial ischemia-reperfusion injury.Frontiers in physiology · 2024Review
- Development of covalent chemogenetic KbioRxiv : the preprint server for biology · 2023Article
- Article
- Evaluation of the Ion Channel Assembly in a Eukaryotic Cell-Free System Focusing on Two-Pore Domain Potassium Channels KInternational journal of molecular sciences · 2023Article
- Synergistic effects of agonists and two-pore-domain potassium channels on secretory responses of human pancreatic duct cells Capan-1.Pflugers Archiv : European journal of physiology · 2023Article
- Axonal membrane stretch suppresses neuronal excitability by activating mechanosensitive K2P channels at the node of Ranvier.Molecular brain · 2023Article
- A Direct Interaction between Cyclodextrins and TASK Channels Decreases the Leak Current in Cerebellar Granule Neurons.Biology · 2022Article
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Authors and funding
8 authors at 5 institutions in 2 countries.
Funding
Abstract
Twik-related K(+) channel 1 (TREK1), TREK2, and Twik-related arachidonic-acid stimulated K(+) channel (TRAAK) form the TREK subfamily of two-pore-domain K(+) (K2P) channels. Despite sharing up to 78% sequence homology and overlapping expression profiles in the nervous system, these channels show major differences in their regulation by physiological stimuli. For instance, TREK1 is inhibited by external acidification, whereas TREK2 is activated. Here, we investigated the ability of the members of the TREK subfamily to assemble to form functional heteromeric channels with novel properties. Using single-molecule pull-down (SiMPull) from HEK cell lysate and subunit counting in the plasma membrane of living cells, we show that TREK1, TREK2, and TRAAK readily coassemble. TREK1 and TREK2 can each heterodimerize with TRAAK, but do so less efficiently than with each other. We functionally characterized the heterodimers and found that all combinations form outwardly rectifying potassium-selective channels but with variable voltage sensitivity and pH regulation. TREK1-TREK2 heterodimers show low levels of activity at physiological external pH but, unlike their corresponding homodimers, are activated by both acidic and alkaline conditions. Modeling based on recent crystal structures, along with mutational analysis, suggests that each subunit within a TREK1-TREK2 channel is regulated independently via titratable His. Finally, TREK1/TRAAK heterodimers differ in function from TRAAK homodimers in two critical ways: they are activated by both intracellular acidification and alkalinization and are regulated by the enzyme phospholipase D2. Thus, heterodimerization provides a means for diversifying functionality through an expansion of the channel types within the K2P channels.
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