Статті в журналах: "TREK-1 potassium channel"

1

Pike, Ashley, Yin Dong, Alexandra Mackenzie, Conor McClenaghan, Shubhashish Mukhopadhyay, Nicola Burgess-Brown, Stephen Tucker, and Elisabeth Carpenter. "Structures of the human two-pore domain potassium channels TREK-1 and TREK-2." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C1489. http://dx.doi.org/10.1107/s2053273314085106.

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TREK-1/2 are members of the mechano-gated subfamily of two-pore (K2P) domain potassium channels leaking K+ out of the cell and contributing to the resting membrane potential. In contrast to the classical tetrameric potassium channels, K2P channels are dimeric with an atypical architecture and the structural mechanisms underlying their channel gating are poorly understood. Here we present the crystal structures of human TREK-1 and TREK-2 at resolutions of 2.7 and 3.4Å which provide insights into the basis of intracellular and extracellular gating in this unique family of ion channels. We have solved the structure of TREK-2 in two distinct conformations differing in the orientation of the pore-lining transmembrane helices. The C-terminal M4 helix is hinged at a conserved glycine residue so that it adopts one of two distinct orientations. The M4 helix is either kinked towards the membrane, packing against the M2 inner helix of the adjacent subunit ("M4 up") or straightens and interacts with the M2/M3 helices from the same subunit ("M4 down"). In the M4 down state, a hydrophobic lateral opening runs perpendicular to the ion conductance pathway between M2 and M4 and links the inner vestibule to the membrane-exposed face of the channel. Transition between the "M4 down" and "M4 up" conformations may play a role in channel activation and gating. Cocrystallisation with a TREK-1/2 channel inhibitor promotes the "M4 down" state. The structure of TREK-1 exhibits an "M4-up" conformation but is unusual in that the selectivity filter is significantly distorted with only two correctly-formed potassium sites. The structure also reveals a divalent ion binding site between the extracellular cap and the pore domain loop. The TREK-1 structure illustrates how changes at an extracellular site can affect the pore structure. The structures will be described in detail along with their implications for channel gating in response to intracellular and extracellular stimuli.

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Levitz, Joshua, Perrine Royal, Yannick Comoglio, Brigitte Wdziekonski, Sébastien Schaub, Daniel M. Clemens, Ehud Y. Isacoff, and Guillaume Sandoz. "Heterodimerization within the TREK channel subfamily produces a diverse family of highly regulated potassium channels." Proceedings of the National Academy of Sciences 113, no. 15 (March 28, 2016): 4194–99. http://dx.doi.org/10.1073/pnas.1522459113.

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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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3

Brenner, Tanja, and Kevin M. O'Shaughnessy. "Both TASK-3 and TREK-1 two-pore loop K channels are expressed in H295R cells and modulate their membrane potential and aldosterone secretion." American Journal of Physiology-Endocrinology and Metabolism 295, no. 6 (December 2008): E1480—E1486. http://dx.doi.org/10.1152/ajpendo.90652.2008.

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The rate of aldosterone synthesis by adrenal glomerulosa cells relies on the selective permeability of the glomerulosa cell to K+ ions. In rodent and bovine adrenal glomerulosa cells, this background potassium current is provided by a two-pore loop potassium (K2P) channel: largely TASK-3 in the rat and TREK-1 in the cow. The nature of the K2P channel in the human adrenal cortex is not known, and we have addressed this issue here using the H295R human adrenal cell line. We show that these cells express mRNA and protein for both TASK-3 and TREK-1 K2P channels. Using a potentiometric dye (FMP), we also show that TASK-3 and TREK-1 channel modulators can affect the membrane potential of H295R cells. Transfecting H295R cells with TASK-3 or TREK-1 dominant-negative mutants (TASK-3 G95E or TREK-1 G144E) produced depolarization of H295R cells and altered K-stimulated aldosterone secretion. Finally, transfection of a constitutively active mutant of Gαq into H295R cells (GTPase-deficient Gαq-QL) depolarized them and increased basal aldosterone secretion. Taken together, our data support both TASK-3 and TREK-1 as being functionally operational in the H295R cell line. This suggests that human adrenal glomerulosa cells may utilize both of these K2P channels for their background potassium current.

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4

Blin, Sandy, Ismail Ben Soussia, Eun-Jin Kim, Frédéric Brau, Dawon Kang, Florian Lesage, and Delphine Bichet. "Mixing and matching TREK/TRAAK subunits generate heterodimeric K2P channels with unique properties." Proceedings of the National Academy of Sciences 113, no. 15 (March 28, 2016): 4200–4205. http://dx.doi.org/10.1073/pnas.1522748113.

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The tandem of pore domain in a weak inwardly rectifying K+ channel (Twik)-related acid-arachidonic activated K+ channel (TRAAK) and Twik-related K+ channels (TREK) 1 and TREK2 are active as homodimers gated by stretch, fatty acids, pH, and G protein-coupled receptors. These two-pore domain potassium (K2P) channels are broadly expressed in the nervous system where they control excitability. TREK/TRAAK KO mice display altered phenotypes related to nociception, neuroprotection afforded by polyunsaturated fatty acids, learning and memory, mood control, and sensitivity to general anesthetics. These channels have emerged as promising targets for the development of new classes of anesthetics, analgesics, antidepressants, neuroprotective agents, and drugs against addiction. Here, we show that the TREK1, TREK2, and TRAAK subunits assemble and form active heterodimeric channels with electrophysiological, regulatory, and pharmacological properties different from those of homodimeric channels. Heteromerization occurs between all TREK variants produced by alternative splicing and alternative translation initiation. These results unveil a previously unexpected diversity of K2P channels that will be challenging to analyze in vivo, but which opens new perspectives for the development of clinically relevant drugs.

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5

Richter, Trevor A., Gennady A. Dvoryanchikov, Nirupa Chaudhari, and Stephen D. Roper. "Acid-Sensitive Two-Pore Domain Potassium (K2P) Channels in Mouse Taste Buds." Journal of Neurophysiology 92, no. 3 (September 2004): 1928–36. http://dx.doi.org/10.1152/jn.00273.2004.

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Sour (acid) taste is postulated to result from intracellular acidification that modulates one or more acid-sensitive ion channels in taste receptor cells. The identity of such channel(s) remains uncertain. Potassium channels, by regulating the excitability of taste cells, are candidates for acid transducers. Several 2-pore domain potassium leak conductance channels (K2P family) are sensitive to intracellular acidification. We examined their expression in mouse vallate and foliate taste buds using RT-PCR, and detected TWIK-1 and -2, TREK-1 and -2, and TASK-1. Of these, TWIK-1 and TASK-1 were preferentially expressed in taste cells relative to surrounding nonsensory epithelium. The related TRESK channel was not detected, whereas the acid-insensitive TASK-2 was. Using confocal imaging with pH-, Ca2+-, and voltage-sensitive dyes, we tested pharmacological agents that are diagnostic for these channels. Riluzole (500 μM), selective for TREK-1 and -2 channels, enhanced acid taste responses. In contrast, halothane (≤ ∼17 mM), which acts on TREK-1 and TASK-1 channels, blocked acid taste responses. Agents diagnostic for other 2-pore domain and voltage-gated potassium channels (anandamide, 10 μM; Gd3+, 1 mM; arachidonic acid, 100 μM; quinidine, 200 μM; quinine, 100 mM; 4-AP, 10 mM; and TEA, 1 mM) did not affect acid responses. The expression of 2-pore domain channels and our pharmacological characterization suggest that a matrix of ion channels, including one or more acid-sensitive 2-pore domain K channels, could play a role in sour taste transduction. However, our results do not unambiguously identify any one channel as the acid taste transducer.

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6

Wiedmann, Felix, Daniel Schlund, Francisco Faustino, Manuel Kraft, Antonius Ratte, Dierk Thomas, Hugo A. Katus, and Constanze Schmidt. "N-Glycosylation of TREK-1/hK2P2.1 Two-Pore-Domain Potassium (K2P) Channels." International Journal of Molecular Sciences 20, no. 20 (October 20, 2019): 5193. http://dx.doi.org/10.3390/ijms20205193.

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Mechanosensitive hTREK-1 two-pore-domain potassium (hK2P2.1) channels give rise to background currents that control cellular excitability. Recently, TREK-1 currents have been linked to the regulation of cardiac rhythm as well as to hypertrophy and fibrosis. Even though the pharmacological and biophysical characteristics of hTREK-1 channels have been widely studied, relatively little is known about their posttranslational modifications. This study aimed to evaluate whether hTREK-1 channels are N-glycosylated and whether glycosylation may affect channel functionality. Following pharmacological inhibition of N-glycosylation, enzymatic digestion or mutagenesis, immunoblots of Xenopus laevis oocytes and HEK-293T cell lysates were used to assess electrophoretic mobility. Two-electrode voltage clamp measurements were employed to study channel function. TREK-1 channel subunits undergo N-glycosylation at asparagine residues 110 and 134. The presence of sugar moieties at these two sites increases channel function. Detection of glycosylation-deficient mutant channels in surface fractions and recordings of macroscopic potassium currents mediated by these subunits demonstrated that nonglycosylated hTREK-1 channel subunits are able to reach the cell surface in general but with seemingly reduced efficiency compared to glycosylated subunits. These findings extend our understanding of the regulation of hTREK-1 currents by posttranslational modifications and provide novel insights into how altered ion channel glycosylation may promote arrhythmogenesis.

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7

Pineda, Ricardo H., Balachandar Nedumaran, Joseph Hypolite, Xiao-Qing Pan, Shandra Wilson, Randall B. Meacham, and Anna P. Malykhina. "Altered expression and modulation of the two-pore-domain (K2P) mechanogated potassium channel TREK-1 in overactive human detrusor." American Journal of Physiology-Renal Physiology 313, no. 2 (August 1, 2017): F535—F546. http://dx.doi.org/10.1152/ajprenal.00638.2016.

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Detrusor overactivity (DO) is the abnormal response of the urinary bladder to physiological stretch during the filling phase of the micturition cycle. The mechanisms of bladder smooth muscle compliance upon the wall stretch are poorly understood. We previously reported that the function of normal detrusor is regulated by TREK-1, a member of the mechanogated subfamily of two-pore-domain potassium (K2P) channels. In the present study, we aimed to identify the changes in expression and function of TREK-1 channels under pathological conditions associated with DO, evaluate the potential relationship between TREK-1 channels and cytoskeletal proteins in the human bladder, and test the possibility of modulation of TREK-1 channel expression by small RNAs. Expression of TREK-1 channels in DO specimens was 2.7-fold decreased compared with control bladders and was associated with a significant reduction of the recorded TREK-1 currents. Isolated DO muscle strips failed to relax when exposed to a TREK-1 channel opener. Immunocytochemical labeling revealed close association of TREK-1 channels with cell cytoskeletal proteins and caveolins, with caveolae microdomains being severely disrupted in DO specimens. Small activating RNA (saRNA) tested in vitro provided evidence that expression of TREK-1 protein could be partially upregulated. Our data confirmed a significant downregulation of TREK-1 expression in human DO specimens and provided evidence of close association between the channel, cell cytoskeleton, and caveolins. Upregulation of TREK-1 expression by saRNA could be a future step for the development of in vivo pharmacological and genetic approaches to treat DO in humans.

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Namiranian, Khodadad, Eric E. Lloyd, Randy F. Crossland, Sean P. Marrelli, George E. Taffet, Anilkumar K. Reddy, Craig J. Hartley, and Robert M. Bryan. "Cerebrovascular responses in mice deficient in the potassium channel, TREK-1." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 299, no. 2 (August 2010): R461—R469. http://dx.doi.org/10.1152/ajpregu.00057.2010.

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We tested the hypothesis that TREK-1, a two-pore domain K channel, is involved with dilations in arteries. Because there are no selective activators or inhibitors of TREK-1, we generated a mouse line deficient in TREK-1. Endothelium-mediated dilations were not different in arteries from wild-type (WT) and TREK-1 knockout (KO) mice. This includes dilations of the middle cerebral artery to ATP, dilations of the basilar artery to ACh, and relaxations of the aorta to carbachol, a cholinergic agonist. The nitric oxide (NO) and endothelium-dependent hyperpolarizing factor components of ATP dilations were identical in the middle cerebral arteries of WT and TREK-1 KO mice. Furthermore, the NO and cyclooxygenase-dependent components were identical in the basilar arteries of the different genotypes. Dilations of the basilar artery to α-linolenic acid, an activator of TREK-1, were not affected by the absence of TREK-1. Whole cell currents recorded using patch-clamp techniques were similar in cerebrovascular smooth muscle cells (CVSMCs) from WT and TREK-1 KO mice. α-linolenic acid or arachidonic acid increased whole cell currents in CVSMCs from both WT and TREK-1 KO mice. The selective blockers of large-conductance Ca-activated K channels, penitrem A and iberiotoxin, blocked the increased currents elicited by either α-linolenic or arachidonic acid. In summary, dilations were similar in arteries from WT and TREK-1 KO mice. There was no sign of TREK-1-like currents in CVSMCs from WT mice, and there were no major differences in currents between the genotypes. We conclude that regulation of arterial diameter is not altered in mice lacking TREK-1.

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9

Yeliashov, S. I., B. R. Sharopov, and Ya M. Shuba. "ROLE OF POTASSIUM CHANNEL TREK-1 IN MECHANOSENSITIVITY OF SMOOTH MUSCLE CELLS FROM RAT DETRUSOR." Fiziolohichnyĭ zhurnal 70, no. 2 (February 5, 2024): 43–50. http://dx.doi.org/10.15407/fz70.02.035.

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Currently, TREK-1 is considered to be the main mechanosensitive channel in detrusor smooth muscle (DSM) cells. The aim of our study was to detect the functioning of the K+-conducting mechanosensitive TREK-1 channel in rat DSM cells using the patch-clamp technique in response to hydrodynamic stimulation (shear stress) and to determine the effects of a TREK-1 agonist – arachidonic acid (AA) and an antagonist – L-methionine. Mechanical stimulation of DSM cells using hydrodynamic stress led to the appearance of a membrane current with signs of pronounced outward rectification at positive membrane potentials, which is typical of TREK-1 activation. The application of AA (50 mcmol/l) activated a current with similar characteristics of the outward rectification to the shear stress-activated one. L-methionine (10 mcmol/l) almost completely prevented the generation of an outwardly rectifying current in response to shear stress stimulation. DSM cells also retained the ability to generate a mechanoactivated current with a more pronounced inward component when extracellular and intracellular K+ were replaced by Cs+. It was concluded that the dominant mechanoactivated current in rat DSM cells is carried by K+-selective TREK-1 channels, but a small portion of this current can also be carried by other nonselective mechanosensitive cation channels.

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Vallee, Nicolas, Cédric Meckler, Jean-Jacques Risso, and Jean-Eric Blatteau. "Neuroprotective role of the TREK-1 channel in decompression sickness." Journal of Applied Physiology 112, no. 7 (April 1, 2012): 1191–96. http://dx.doi.org/10.1152/japplphysiol.01100.2011.

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Nitrogen supersaturation and bubble formation can occur in the vascular system after diving, leading to death and nervous disorders from decompression sickness (DCS). Bubbles alter the vascular endothelium, activate platelets, and lead to focal ischemia with neurological damage mediated by the mechanosensitive TREK-1 neuronal potassium ion channel that sets pre- and postsynaptic resting membrane potentials. We report a neuroprotective effect associated with TREK-1. C57Bl6 mice were subjected to decompression from a simulated 90 msw dive. Of 143 mice that were wild type (WT) for TREK-1, 51.7% showed no DCS, 27.3% failed a grip test, and 21.0% died. Of 88 TREK-1 knockouts (KO), 26.1% showed no DCS, 42.0% failed a grip test, and 31.8% died. Mice that did not express TREK-1 had lower DCS resistance and were more likely to develop neurological symptoms. We conclude that the TREK-1 potassium channel was neuroprotective for DCS.

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Yamamoto, Y., and K. Taniguchi. "Expression of Tandem P Domain K+ Channel, TREK-1, in the Rat Carotid Body." Journal of Histochemistry & Cytochemistry 54, no. 4 (January 6, 2006): 467–72. http://dx.doi.org/10.1369/jhc.5a6755.2005.

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TREK-1 is one of the important potassium channels for regulating membrane excitability. To examine the distribution of TREK-1 in the rat carotid body, we performed RT-PCR for mRNA expression and in situ hybridization and immunohistochemistry for tissue distribution of TREK-1. RT-PCR detected mRNA expression of TREK-1 in the carotid body. Furthermore, in situ hybridization revealed the localization of TREK-1 mRNA in the glomus cells. TREK-1 immunoreactivity was mainly distributed in the glomus cells and nerve fibers in the carotid body. TREK-1 may modulate potassium current of glomus cells and/or afferent nerve endings in the rat carotid body.

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12

Yang, Jun Ho, Adrian S. Siregar, Eun-Jin Kim, Marie Merci Nyiramana, Eui-Jung Shin, Jaehee Han, Ju-Tae Sohn, Jong Woo Kim, and Dawon Kang. "Involvement of TREK-1 Channel in Cell Viability of H9c2 Rat Cardiomyoblasts Affected by Bupivacaine and Lipid Emulsion." Cells 8, no. 5 (May 14, 2019): 454. http://dx.doi.org/10.3390/cells8050454.

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Lipid emulsion (LE) therapy has been used to reduce overdose of bupivacaine (BPV)-induced cardiotoxicity. The TWIK-related potassium channel-1 (TREK-1) is inhibited by BPV and activated by polyunsaturated fatty acids, which are the main component in LE. These pharmacological properties inspired us to investigate whether the TREK-1 channel is associated with cell viability of H9c2 cardiomyoblasts affected by BPV and LE. Consistent with previous studies, BPV-induced cell death was reduced by LE treatment. The reduction in the TREK-1 expression level by BPV was alleviated by LE. The BPV cytotoxicity highly decreased in TREK-1 overexpressed cells but was the opposite in TREK-1 knocked-down cells. TREK-1 channel activators and inhibitors increased and decreased cell viability, respectively. BPV-induced depolarization of the plasma and mitochondrial membrane potential and increase in intracellular Ca2+ level were blocked by LE treatment. BPV-induced depolarization of membrane potential was reduced in TREK-1 overexpressed cells, indicating that TREK-1 channels mediate setting the resting membrane potentials as a background K+ channel in H9c2 cells. These results show that TREK-1 activity is involved in the BPV cytotoxicity and the antagonistic effect of LE in H9c2 cells and suggest that TREK-1 could be a target for action of BPV and LE.

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13

Schwingshackl, Andreas, Bin Teng, Manik Ghosh, Alina Nico West, Patrudu Makena, Vijay Gorantla, Scott E. Sinclair, and Christopher M. Waters. "Regulation and function of the two-pore-domain (K2P) potassium channel Trek-1 in alveolar epithelial cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 302, no. 1 (January 1, 2012): L93—L102. http://dx.doi.org/10.1152/ajplung.00078.2011.

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Hyperoxia can lead to a myriad of deleterious effects in the lung including epithelial damage and diffuse inflammation. The specific mechanisms by which hyperoxia promotes these pathological changes are not completely understood. Activation of ion channels has been proposed as one of the mechanisms required for cell activation and mediator secretion. The two-pore-domain K+ channel (K2P) Trek-1 has recently been described in lung epithelial cells, but its function remains elusive. In this study we hypothesized that hyperoxia affects expression of Trek-1 in alveolar epithelial cells and that Trek-1 is involved in regulation of cell proliferation and cytokine secretion. We found gene expression of several K2P channels in mouse alveolar epithelial cells (MLE-12), and expression of Trek-1 was significantly downregulated in cultured cells and lungs of mice exposed to hyperoxia. Similarly, proliferation cell nuclear antigen (PCNA) and Cyclin D1 expression were downregulated by exposure to hyperoxia. We developed an MLE-12 cell line deficient in Trek-1 expression using shRNA and found that Trek-1 deficiency resulted in increased cell proliferation and upregulation of PCNA but not Cyclin D1. Furthermore, IL-6 and regulated on activation normal T-expressed and presumably secreted (RANTES) secretion was decreased in Trek-1-deficient cells, whereas release of monocyte chemoattractant protein-1 was increased. Release of KC/IL-8 was not affected by Trek-1 deficiency. Overall, deficiency of Trek-1 had a more pronounced effect on mediator secretion than exposure to hyperoxia. This is the first report suggesting that the K+ channel Trek-1 could be involved in regulation of alveolar epithelial cell proliferation and cytokine secretion, but a direct association with hyperoxia-induced changes in Trek-1 levels remains elusive.

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Yarishkin, Oleg, Tam T. T. Phuong, Colin A. Bretz, Kenneth W. Olsen, Jackson M. Baumann, Monika Lakk, Alan Crandall, Catherine Heurteaux, Mary E. Hartnett, and David Križaj. "TREK-1 channels regulate pressure sensitivity and calcium signaling in trabecular meshwork cells." Journal of General Physiology 150, no. 12 (November 16, 2018): 1660–75. http://dx.doi.org/10.1085/jgp.201812179.

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Mechanotransduction by the trabecular meshwork (TM) is an essential component of intraocular pressure regulation in the vertebrate eye. This process is compromised in glaucoma but is poorly understood. In this study, we identify transient receptor potential vanilloid isoform 4 (TRPV4) and TWIK-related potassium channel-1 (TREK-1) as key molecular determinants of TM membrane potential, pressure sensitivity, calcium homeostasis, and transcellular permeability. We show that resting membrane potential in human TM cells is unaffected by “classical” inhibitors of voltage-activated, calcium-activated, and inwardly rectifying potassium channels but is depolarized by blockers of tandem-pore K+ channels. Using gene profiling, we reveal the presence of TREK-1, TASK-1, TWIK-2, and THIK transcripts in TM cells. Pressure stimuli, arachidonic acid, and TREK-1 activators hyperpolarize these cells, effects that are antagonized by quinine, amlodipine, spadin, and short-hairpin RNA–mediated knockdown of TREK-1 but not TASK-1. Activation and inhibition of TREK-1 modulates [Ca2+]TM and lowers the impedance of cell monolayers. Together, these results suggest that tensile homeostasis in the TM may be regulated by balanced, pressure-dependent activation of TRPV4 and TREK-1 mechanotransducers.

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Magra, Merzesh, Steven Hughes, Alicia J. El Haj, and Nicola Maffulli. "VOCCs and TREK-1 ion channel expression in human tenocytes." American Journal of Physiology-Cell Physiology 292, no. 3 (March 2007): C1053—C1060. http://dx.doi.org/10.1152/ajpcell.00053.2006.

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Mechanosensitive and voltage-gated ion channels are known to perform important roles in mechanotransduction in a number of connective tissues, including bone and muscle. It is hypothesized that voltage-gated and mechanosensitive ion channels also may play a key role in some or all initial responses of human tenocytes to mechanical stimulation. However, to date there has been no direct investigation of ion channel expression by human tenocytes. Human tenocytes were cultured from patellar tendon samples harvested from five patients undergoing routine total knee replacement surgery (mean age: 66 yr; range: 63–73 yr). RT-PCR, Western blotting, and whole cell electrophysiological studies were performed to investigate the expression of different classes of ion channels within tenocytes. Human tenocytes expressed mRNA and protein encoding voltage-operated calcium channel (VOCC) subunits (Ca α1A, Ca α1C, Ca α1D, Ca α2δ1) and the mechanosensitive tandem pore domain potassium channel (2PK+) TREK-1. They exhibit whole cell currents consistent with the functional expression of these channels. In addition, other ionic currents were detected within tenocytes consistent with the expression of a diverse array of other ion channels. VOCCs and TREK channels have been implicated in mechanotransduction signaling pathways in numerous connective tissue cell types. These mechanisms may be present in human tenocytes. In addition, human tenocytes may express other channel currents. Ion channels may represent potential targets for the pharmacological management of chronic tendinopathies.

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Mathie, Alistair, Emma L. Veale, Kevin P. Cunningham, Robyn G. Holden, and Paul D. Wright. "Two-Pore Domain Potassium Channels as Drug Targets: Anesthesia and Beyond." Annual Review of Pharmacology and Toxicology 61, no. 1 (January 6, 2021): 401–20. http://dx.doi.org/10.1146/annurev-pharmtox-030920-111536.

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Two-pore domain potassium (K2P) channels stabilize the resting membrane potential of both excitable and nonexcitable cells and, as such, are important regulators of cell activity. There are many conditions where pharmacological regulation of K2P channel activity would be of therapeutic benefit, including, but not limited to, atrial fibrillation, respiratory depression, pulmonary hypertension, neuropathic pain, migraine, depression, and some forms of cancer. Up until now, few if any selective pharmacological regulators of K2P channels have been available. However, recent publications of solved structures with small-molecule activators and inhibitors bound to TREK-1, TREK-2, and TASK-1 K2P channels have given insight into the pharmacophore requirements for compound binding to these sites. Together with the increasing availability of a number of novel, active, small-molecule compounds from K2P channel screening programs, these advances have opened up the possibility of rational activator and inhibitor design to selectively target K2P channels.

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17

Lesage, Florian, and Michel Lazdunski. "Molecular and functional properties of two-pore-domain potassium channels." American Journal of Physiology-Renal Physiology 279, no. 5 (November 1, 2000): F793—F801. http://dx.doi.org/10.1152/ajprenal.2000.279.5.f793.

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The two-pore-domain K+ channels, or K2P channels, constitute a novel class of K+channel subunits. They have four transmembrane segments and are active as dimers. The tissue distribution of these channels is widespread, and they are found in both excitable and nonexcitable cells. K2P channels produce currents with unusual characteristics. They are quasi-instantaneous and noninactivating, and they are active at all membrane potentials and insensitive to the classic K+ channel blockers. These properties designate them as background K+ channels. They are expected to play a major role in setting the resting membrane potential in many cell types. Another salient feature of K2P channels is the diversity of their regulatory mechanisms. The weak inward rectifiers TWIK-1 and TWIK-2 are stimulated by activators of protein kinase C and decreased by internal acidification, the baseline TWIK-related acid-sensitive K+ (TASK)-1 and TASK-2 channels are sensitive to external pH changes in a narrow range near physiological pH, and the TWIK-related (TREK)-1 and TWIK-related arachidonic acid-stimulated K+ (TRAAK) channels are the first cloned polyunsaturated fatty acids-activated and mechanogated K+ channels. The recent demonstration that TASK-1 and TREK-1 channels are activated by inhalational general anesthetics, and that TRAAK is activated by the neuroprotective agent riluzole, indicates that this novel class of K+ channels is an interesting target for new therapeutic developments.

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Bryan, Robert M., Junping You, Sharon C. Phillips, Jon J. Andresen, Eric E. Lloyd, Paul A. Rogers, Stuart E. Dryer, and Sean P. Marrelli. "Evidence for two-pore domain potassium channels in rat cerebral arteries." American Journal of Physiology-Heart and Circulatory Physiology 291, no. 2 (August 2006): H770—H780. http://dx.doi.org/10.1152/ajpheart.01377.2005.

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Little is known about the presence and function of two-pore domain K+ (K2P) channels in vascular smooth muscle cells (VSMCs). Five members of the K2P channel family are known to be directly activated by arachidonic acid (AA). The purpose of this study was to determine 1) whether AA-sensitive K2P channels are expressed in cerebral VSMCs and 2) whether AA dilates the rat middle cerebral artery (MCA) by increasing K+ currents in VSMCs via an atypical K+ channel. RT-PCR revealed message for the following AA-sensitive K2P channels in rat MCA: tandem of P domains in weak inward rectifier K+ (TWIK-2), TWIK-related K+ (TREK-1 and TREK-2), TWIK-related AA-stimulated K+ (TRAAK), and TWIK-related halothane-inhibited K+ (THIK-1) channels. However, in isolated VSMCs, only message for TWIK-2 was found. Western blotting showed that TWIK-2 is present in MCA, and immunohistochemistry further demonstrated its presence in VSMCs. AA (10–100 μM) dilated MCAs through an endothelium-independent mechanism. AA-induced dilation was not affected by inhibition of cyclooxygenase, epoxygenase, or lipoxygenase or inhibition of classical K+ channels with 10 mM TEA, 3 mM 4-aminopyridine, 10 μM glibenclamide, or 100 μM Ba2+. AA-induced dilations were blocked by 50 mM K+, indicating involvement of a K+ channel. AA (10 μM) increased whole cell K+ currents in dispersed cerebral VSMCs. AA-induced currents were not affected by inhibitors of the AA metabolic pathways or blockade of classical K+ channels. We conclude that AA dilates the rat MCA and increases K+ currents in VSMCs via an atypical K+ channel that is likely a member of the K2P channel family.

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Ullrich, Jessica, Carsten Ohlhoff, Srujan Kumar Dondapati, Anne Zemella, and Stefan Kubick. "Evaluation of the Ion Channel Assembly in a Eukaryotic Cell-Free System Focusing on Two-Pore Domain Potassium Channels K2P." International Journal of Molecular Sciences 24, no. 7 (March 27, 2023): 6299. http://dx.doi.org/10.3390/ijms24076299.

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Oligomeric ion channels are abundant in nature. However, the recombinant expression in cell culture-based systems remains tedious and challenging due to negative side effects, limiting the understanding of their role in health and disease. Accordingly, in this work, we demonstrate the cell-free synthesis (CFS) as an alternative platform to study the assembly of two-pore domain potassium channels (K2P) within endogenous endoplasmic reticulum-derived microsomes. Exploiting the open nature of CFS, we investigate the cotranslational translocation of TREK-2 into the microsomes and suggest a cotranslational assembly with typical single-channel behavior in planar lipid-bilayer electrophysiology. The heteromeric assembly of K2P channels is a contentious matter, accordingly we prove the successful assembly of TREK-2 with TWIK-1 using a biomolecular fluorescence complementation assay, Western blot analysis and autoradiography. The results demonstrate that TREK-2 homodimer assembly is the initial step, followed by heterodimer formation with the nascent TWIK-1, providing evidence of the intergroup heterodimerization of TREK-2 and TWIK-1 in eukaryotic CFS. Since K2P channels are involved in various pathophysiological conditions, including pain and nociception, CFS paves the way for in-depth functional studies and related pharmacological interventions. This study highlights the versatility of the eukaryotic CFS platform for investigating ion channel assembly in a native-like environment.

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20

Afzali, Ali M., Tobias Ruck, Alexander M. Herrmann, Janette Iking, Claudia Sommer, Christoph Kleinschnitz, Corinna Preuβe, et al. "The potassium channels TASK2 and TREK1 regulate functional differentiation of murine skeletal muscle cells." American Journal of Physiology-Cell Physiology 311, no. 4 (October 1, 2016): C583—C595. http://dx.doi.org/10.1152/ajpcell.00363.2015.

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Two-pore domain potassium (K2P) channels influence basic cellular parameters such as resting membrane potential, cellular excitability, or intracellular Ca2+-concentration [Ca2+]i. While the physiological importance of K2P channels in different organ systems (e.g., heart, central nervous system, or immune system) has become increasingly clear over the last decade, their expression profile and functional role in skeletal muscle cells (SkMC) remain largely unknown. The mouse SkMC cell line C2C12, wild-type mouse muscle tissue, and primary mouse muscle cells (PMMs) were analyzed using quantitative PCR, Western blotting, and immunohistochemical stainings as well as functional analysis including patch-clamp measurements and Ca2+ imaging. Mouse SkMC express TWIK-related acid-sensitive K+ channel (TASK) 2, TWIK-related K+ channel (TREK) 1, TREK2, and TWIK-related arachidonic acid stimulated K+ channel (TRAAK). Except TASK2 all mentioned channels were upregulated in vitro during differentiation from myoblasts to myotubes. TASK2 and TREK1 were also functionally expressed and upregulated in PMMs isolated from mouse muscle tissue. Inhibition of TASK2 and TREK1 during differentiation revealed a morphological impairment of myoblast fusion accompanied by a downregulation of maturation markers. TASK2 and TREK1 blockade led to a decreased K+ outward current and a decrease of ACh-dependent Ca2+ influx in C2C12 cells as potential underlying mechanisms. K2P-channel expression was also detected in human muscle tissue by immunohistochemistry pointing towards possible relevance for human muscle cell maturation and function. In conclusion, our findings for the first time demonstrate the functional expression of TASK2 and TREK1 in muscle cells with implications for differentiation processes warranting further investigations in physiologic and pathophysiologic scenarios.

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Schwingshackl, Andreas, Bin Teng, Manik Ghosh, Keng Gat Lim, Gabor Tigyi, Damodaran Narayanan, Jonathan H. Jaggar, and Christopher M. Waters. "Regulation of interleukin-6 secretion by the two-pore-domain potassium channel Trek-1 in alveolar epithelial cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 304, no. 4 (February 15, 2013): L276—L286. http://dx.doi.org/10.1152/ajplung.00299.2012.

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We recently proposed a role for the two-pore-domain K+ (K2P) channel Trek-1 in the regulation of cytokine release from mouse alveolar epithelial cells (AECs) by demonstrating decreased interleukin-6 (IL-6) secretion from Trek-1-deficient cells, but the underlying mechanisms remained unknown. This study was designed to investigate the mechanisms by which Trek-1 decreases IL-6 secretion. We hypothesized that Trek-1 regulates tumor necrosis factor-α (TNF-α)-induced IL-6 release via NF-κB-, p38-, and PKC-dependent pathways. We found that Trek-1 deficiency decreased IL-6 secretion from mouse and human AECs at both transcriptional and translational levels. While NF-κB/p65 phosphorylation was unchanged, p38 phosphorylation was decreased in Trek-1-deficient cells, and pharmacological inhibition of p38 decreased IL-6 secretion in control but not Trek-1-deficient cells. Similarly, pharmacological inhibition of PKC also decreased IL-6 release, and we found decreased phosphorylation of the isoforms PKC/PKDμ (Ser744/748), PKCθ, PKCδ, PKCα/βII, and PKCζ/λ, but not PKC/PKDμ (Ser916) in Trek-1-deficient AECs. Phosphorylation of PKCθ, a Ca2+-independent isoform, was intact in control cells but impaired in Trek-1-deficient cells. Furthermore, TNF-α did not elevate the intracellular Ca2+ concentration in control or Trek-1-deficient cells, and removal of extracellular Ca2+ did not impair IL-6 release. In summary, we report the expression of Trek-1 in human AECs and propose that Trek-1 deficiency may alter both IL-6 translation and transcription in AECs without affecting Ca2+ signaling. The results of this study identify Trek-1 as a new potential target for the development of novel treatment strategies against acute lung injury.

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Lolicato, Marco, Andrew M. Natale, Fayal Abderemane-Ali, David Crottès, Sara Capponi, Ramona Duman, Armin Wagner, John M. Rosenberg, Michael Grabe, and Daniel L. Minor. "K2P channel C-type gating involves asymmetric selectivity filter order-disorder transitions." Science Advances 6, no. 44 (October 2020): eabc9174. http://dx.doi.org/10.1126/sciadv.abc9174.

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K2P potassium channels regulate cellular excitability using their selectivity filter (C-type) gate. C-type gating mechanisms, best characterized in homotetrameric potassium channels, remain controversial and are attributed to selectivity filter pinching, dilation, or subtle structural changes. The extent to which such mechanisms control C-type gating of innately heterodimeric K2Ps is unknown. Here, combining K2P2.1 (TREK-1) x-ray crystallography in different potassium concentrations, potassium anomalous scattering, molecular dynamics, and electrophysiology, we uncover unprecedented, asymmetric, potassium-dependent conformational changes that underlie K2P C-type gating. These asymmetric order-disorder transitions, enabled by the K2P heterodimeric architecture, encompass pinching and dilation, disrupt the S1 and S2 ion binding sites, require the uniquely long K2P SF2-M4 loop and conserved “M3 glutamate network,” and are suppressed by the K2P C-type gate activator ML335. These findings demonstrate that two distinct C-type gating mechanisms can operate in one channel and underscore the SF2-M4 loop as a target for K2P channel modulator development.

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Namiranian, Khodadad, Christa D. Brink, Jerry Clay Goodman, Claudia S. Robertson, and Robert M. Bryan. "Traumatic Brain Injury in Mice Lacking the K Channel, TREK-1." Journal of Cerebral Blood Flow & Metabolism 31, no. 3 (December 15, 2010): e1-e6. http://dx.doi.org/10.1038/jcbfm.2010.223.

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The purpose of this study was to determine whether the potassium channel, TREK-1, was neuroprotective after traumatic brain injury (TBI). Since there are no selective blockers, we used TREK-1 knockout (KO) mice for our study. Wild-type (WT) and TREK-1 KO mice were anesthetized and subjected to controlled-cortical impact injury (deformation of the brain by 1.5 mm by a 3-mm diameter rod traveling at a 3 m/s). Laser Doppler perfusion (LDP) decreased by ∼80% in the injured cortex and remained at that level in both WT and TREK-1 KO mice ( n=10 and 11, respectively). Laser Doppler perfusion decreased by 50% to 60% in cortical areas directly adjacent to the site of injury. There were no statistical differences in LDP between genotype. The contusion volume, determined 15 days after the TBI using hematoxylin and eosin-stained coronal brain sections, was 4.1±0.8 ( n=10) and 5.1±0.5 ( n=11) mm3 for WT and TREK-1 KO, respectively (not significant, P=0.34). Cell counts of viable neurons in the CA1 and CA3 regions of the hippocampus were similar between WT and TREK-1 KO mice ( P=0.51 and 0.84 for CA1 and CA3, respectively). We conclude that TREK-1 expression does not provide brain protection after TBI.

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Zhang, Yunna, Jiafeng Fu, Yang Han, Dandan Feng, Shaojie Yue, Yan Zhou, and Ziqiang Luo. "Two-Pore-Domain Potassium Channel TREK–1 Mediates Pulmonary Fibrosis through Macrophage M2 Polarization and by Direct Promotion of Fibroblast Differentiation." Biomedicines 11, no. 5 (April 26, 2023): 1279. http://dx.doi.org/10.3390/biomedicines11051279.

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Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by myofibroblast proliferation and abnormal accumulation of extracellular matrix in the lungs. After lung injury, M2 macrophages mediate the pathogenesis of pulmonary fibrosis by secreting fibrotic cytokines that promote myofibroblast activation. The TWIK-related potassium channel (TREK–1, also known as KCNK2) is a K2P channel that is highly expressed in cardiac, lung, and other tissues; it worsens various tumors, such as ovarian cancer and prostate cancer, and mediates cardiac fibrosis. However, the role of TREK–1 in lung fibrosis remains unclear. This study aimed to examine the effects of TREK–1 on bleomycin (BLM)-induced lung fibrosis. The results show that TREK–1 knockdown, mediated by the adenovirus or pharmacological inhibition of TREK–1 with fluoxetine, resulted in diminished BLM-induced lung fibrosis. TREK–1 overexpression in macrophages remarkably increased the M2 phenotype, resulting in fibroblast activation. Furthermore, TREK–1 knockdown and fluoxetine administration directly reduced the differentiation of fibroblasts to myofibroblasts by inhibiting the focal adhesion kinase (FAK)/p38 mitogen-activated protein kinases (p38)/Yes-associated protein (YAP) signaling pathway. In conclusion, TREK–1 plays a central role in the pathogenesis of BLM-induced lung fibrosis, which serves as a theoretical basis for the inhibition of TREK–1 as a potential therapy protocol for lung fibrosis.

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Lengyel, Miklós, Gábor Czirják, and Péter Enyedi. "Formation of Functional Heterodimers by TREK-1 and TREK-2 Two-pore Domain Potassium Channel Subunits." Journal of Biological Chemistry 291, no. 26 (April 28, 2016): 13649–61. http://dx.doi.org/10.1074/jbc.m116.719039.

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26

Blondeau, Nicolas, Olivier Pétrault, Stella Manta, Valérie Giordanengo, Pierre Gounon, Régis Bordet, Michel Lazdunski, and Catherine Heurteaux. "Polyunsaturated Fatty Acids Are Cerebral Vasodilators via the TREK-1 Potassium Channel." Circulation Research 101, no. 2 (July 20, 2007): 176–84. http://dx.doi.org/10.1161/circresaha.107.154443.

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XIANTAOLI, V. DYACHENKO, M. ZUZARTE, C. PUTZKE, R. PREISIGMULLER, G. ISENBERG, and J. DAUT. "The stretch-activated potassium channel TREK-1 in rat cardiac ventricular muscle." Cardiovascular Research 69, no. 1 (January 2006): 86–97. http://dx.doi.org/10.1016/j.cardiores.2005.08.018.

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Wang, Ying, Zhijie Fu, Zhiyong Ma, Na Li, and Hong Shang. "Bepridil, a class IV antiarrhythmic agent, can block the TREK-1 potassium channel." Annals of Translational Medicine 9, no. 14 (July 2021): 1123. http://dx.doi.org/10.21037/atm-20-7971.

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Monaghan, Kevin, Salah A. Baker, Laura Dwyer, William C. Hatton, Kyung Sik Park, Kenton M. Sanders, and Sang Don Koh. "The stretch-dependent potassium channel TREK-1 and its function in murine myometrium." Journal of Physiology 589, no. 5 (February 25, 2011): 1221–33. http://dx.doi.org/10.1113/jphysiol.2010.203869.

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Enyeart, John J., and Judith A. Enyeart. "Human adrenal glomerulosa cells express K2P and GIRK potassium channels that are inhibited by ANG II and ACTH." American Journal of Physiology-Cell Physiology 321, no. 1 (July 1, 2021): C158—C175. http://dx.doi.org/10.1152/ajpcell.00118.2021.

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In whole cell patch clamp recordings, it was discovered that normal human adrenal zona glomerulosa (AZG) cells express members of the three major families of K+ channels. Among these are a two-pore (K2P) leak-type and a G protein-coupled, inwardly rectifying (GIRK) channel, both inhibited by peptide hormones that stimulate aldosterone secretion. The K2P current displayed properties identifying it as TREK-1 (KCNK2). This outwardly rectifying current was activated by arachidonic acid and inhibited by angiotensin II (ANG II), adrenocorticotrophic hormone (ACTH), and forskolin. The activation and inhibition of TREK-1 was coupled to AZG cell hyperpolarization and depolarization, respectively. A second K2P channel, TASK-1 (KCNK3), was expressed at a lower density in AZG cells. Human AZG cells also express inwardly rectifying K+ current(s) (KIR) that include quasi-instantaneous and time-dependent components. This is the first report demonstrating the presence of KIR in whole cell recordings from AZG cells of any species. The time-dependent current was selectively inhibited by ANG II, and ACTH, identifying it as a G protein-coupled (GIRK) channel, most likely KIR3.4 (KCNJ5). The quasi-instantaneous KIR current was not inhibited by ANG II or ACTH and may be a separate non-GIRK current. Finally, AZG cells express a voltage-gated, rapidly inactivating K+ current whose properties identified as KV1.4 (KCNA4), a conclusion confirmed by Northern blot. These findings demonstrate that human AZG cells express K2P and GIRK channels whose inhibition by ANG II and ACTH is likely coupled to depolarization-dependent secretion. They further demonstrate that human AZG K+ channels differ fundamentally from the widely adopted rodent models for human aldosterone secretion.

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Vivier, Delphine, Khalil Bennis, Florian Lesage, and Sylvie Ducki. "Perspectives on the Two-Pore Domain Potassium Channel TREK-1 (TWIK-Related K+Channel 1). A Novel Therapeutic Target?" Journal of Medicinal Chemistry 59, no. 11 (December 14, 2015): 5149–57. http://dx.doi.org/10.1021/acs.jmedchem.5b00671.

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Kim, Ajung, Hyun-Gug Jung, Yeong-Eun Kim, Seung-Chan Kim, Jae-Yong Park, Seok-Geun Lee, and Eun Mi Hwang. "The Knockdown of TREK-1 in Hippocampal Neurons Attenuate Lipopolysaccharide-Induced Depressive-Like Behavior in Mice." International Journal of Molecular Sciences 20, no. 23 (November 24, 2019): 5902. http://dx.doi.org/10.3390/ijms20235902.

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TWIK-related potassium channel-1 (TREK-1) is broadly expressed in the brain and involved in diverse brain diseases, such as seizures, ischemia, and depression. However, the cell type-specific roles of TREK-1 in the brain are largely unknown. Here, we generated a Cre-dependent TREK-1 knockdown (Cd-TREK-1 KD) transgenic mouse containing a gene cassette for Cre-dependent TREK-1 short hairpin ribonucleic acid to regulate the cell type-specific TREK-1 expression. We confirmed the knockdown of TREK-1 by injecting adeno-associated virus (AAV) expressing Cre into the hippocampus of the mice. To study the role of hippocampal neuronal TREK-1 in a lipopolysaccharide (LPS)-induced depression model, we injected AAV-hSyn-BFP (nCTL group) or AAV-hSyn-BFP-Cre (nCre group) virus into the hippocampus of Cd-TREK-1 KD mice. Interestingly, the immobility in the tail suspension test after LPS treatment did not change in the nCre group. Additionally, some neurotrophic factors (BDNF, VEGF, and IGF-1) significantly increased more in the nCre group compared to the nCTL group after LPS treatment, but there was no difference in the expression of their receptors. Therefore, our data suggest that TREK-1 in the hippocampal neurons has antidepressant effects, and that Cd-TREK-1 KD mice are a valuable tool to reveal the cell type-specific roles of TREK-1 in the brain.

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Borsotto, M., A. Djillani, C. Devader, C. Heurteaux, and J. Mazella. "The Mini-Spadin, an efficient alternate to Spadin in the depression treatment." European Psychiatry 33, S1 (March 2016): S407. http://dx.doi.org/10.1016/j.eurpsy.2016.01.1470.

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ObjectivesWe previously discovered spadin as a new antidepressant drug concept. Spadin exerts its antidepressant actions on the TREK-1 potassium channel, a new antidepressant (AD) target. We have shown that spadin acts more rapidly in comparison to other ADs. We have pointed out that spadin induced neurogenesis after only 4-day treatments. We have demonstrated that spadin did not display side effects at the cardiac level and on TREK-1 controlled functions such as stroke, epilepsy or pain.ObjectivesWith the final goal to make spadin a drug for human clinic, our objective was to find analogs of spadin demonstrating a better affinity or a better in vivo stability or both.MethodsSeveral analogs of spadin were synthesized. Their ability to block the TREK-1 channel activity were first tested by electrophysiology on HEK293 cells stably transfected with TREK-1 channels. AD effects were measured by using the forced swim test and the novelty suppressed feeding test. Neurogenesis was investigated by measuring the expression level of the synaptic protein PSD-95 in in vitro cultured neurons.ResultsOur data allow us to identify a shortened spadin, called mini-spadin, that displayed the same AD properties as spadin and a 400 fold increase in the TREK-1 affinity. Mini-spadin increased the synaptogenesis marker PSD95 levels after only 24 hours of treatment, suggesting that like spadin, mini-spadin was able to induce neurogenesis and synaptogenesis.ConclusionsEven if further experiments are required, the mini-spadin appears to be more efficient than spadin offering a very promising alternate to spadin as human drug.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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Abraham, Dennis M., Teresa E. Lee, Lewis J. Watson, Lan Mao, Gurangad Chandok, Hong-Gang Wang, Stephan Frangakis, et al. "The two-pore domain potassium channel TREK-1 mediates cardiac fibrosis and diastolic dysfunction." Journal of Clinical Investigation 128, no. 11 (October 2, 2018): 4843–55. http://dx.doi.org/10.1172/jci95945.

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Heurteaux, Catherine, Guillaume Lucas, Nicolas Guy, Malika El Yacoubi, Susanne Thümmler, Xiao-Dong Peng, Florence Noble, et al. "Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotype." Nature Neuroscience 9, no. 9 (August 13, 2006): 1134–41. http://dx.doi.org/10.1038/nn1749.

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Ji, Xin-cai, Wan-hong Zhao, Dong-xu Cao, Qiao-qiao Shi, and Xiao-liang Wang. "Novel neuroprotectant chiral 3-n-butylphthalide inhibits tandem-pore-domain potassium channel TREK-1." Acta Pharmacologica Sinica 32, no. 2 (February 2011): 182–87. http://dx.doi.org/10.1038/aps.2010.210.

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Zhiyong, M. A., Zhijie Fu, Na Li, Shanying Huang, Li Li, Yun Zhang, and Zhijie Fu. "GW29-e1702 Bepridil a class IV antiarrhythmic agent can block TREK-1 potassium channel." Journal of the American College of Cardiology 72, no. 16 (October 2018): C55. http://dx.doi.org/10.1016/j.jacc.2018.08.201.

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Wu, Xiao, Ronghua Tang, Yang Liu, Jingjiao Song, Zhiyuan Yu, Wei Wang, and Minjie Xie. "Small RNA interference-mediated gene silencing of TREK-1 potassium channel in cultured astrocytes." Journal of Huazhong University of Science and Technology [Medical Sciences] 32, no. 6 (December 2012): 849–55. http://dx.doi.org/10.1007/s11596-012-1046-y.

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Zhao, Ke-Qing, Guoxiang Xiong, Morgan Wilber, Noam A. Cohen, and James L. Kreindler. "A role for two-pore K+ channels in modulating Na+ absorption and Cl− secretion in normal human bronchial epithelial cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 302, no. 1 (January 1, 2012): L4—L12. http://dx.doi.org/10.1152/ajplung.00102.2011.

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Mucociliary clearance is the primary innate physical defense mechanism against inhaled pathogens and toxins. Vectorial ion transport, primarily sodium absorption and anion secretion, by airway epithelial cells supports mucociliary clearance. This is evidenced by diseases of abnormal ion transport such as cystic fibrosis and pseudohypoaldosteronism that are characterized by changes in mucociliary clearance. Sodium absorption and chloride secretion in human bronchial epithelial cells depend on potassium channel activity, which creates a favorable electrochemical gradient for both by hyperpolarizing the apical plasma membrane. Although the role of basolateral membrane potassium channels is firmly established and extensively studied, a role for apical membrane potassium channels has also been described. Here, we demonstrate that bupivacaine and quinidine, blockers of four-transmembrane domain, two-pore potassium (K2P) channels, inhibit both amiloride-sensitive sodium absorption and forskolin-stimulated anion secretion in polarized, normal human bronchial epithelial cells at lower concentrations when applied to the mucosal surface than when applied to the serosal surface. Transcripts from four genes, KCNK1 (TWIK-1), KCNK2 (TREK-1), KCNK5 (TASK-2), and KCNK6 (TWIK-2), encoding K2P channels were identified by RT-PCR. Protein expression at the apical membrane was confirmed by immunofluorescence. Our data provide further evidence that potassium channels, in particular K2P channels, are expressed and functional in the apical membrane of airway epithelial cells where they may be targets for therapeutic manipulation.

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40

Wiedmann, Felix, Norbert Frey, and Constanze Schmidt. "Two-Pore-Domain Potassium (K2P-) Channels: Cardiac Expression Patterns and Disease-Specific Remodelling Processes." Cells 10, no. 11 (October 27, 2021): 2914. http://dx.doi.org/10.3390/cells10112914.

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Two-pore-domain potassium (K2P-) channels conduct outward K+ currents that maintain the resting membrane potential and modulate action potential repolarization. Members of the K2P channel family are widely expressed among different human cell types and organs where they were shown to regulate important physiological processes. Their functional activity is controlled by a broad variety of different stimuli, like pH level, temperature, and mechanical stress but also by the presence of lipids or pharmacological agents. In patients suffering from cardiovascular diseases, alterations in K2P-channel expression and function have been observed, suggesting functional significance and a potential therapeutic role of these ion channels. For example, upregulation of atrial specific K2P3.1 (TASK-1) currents in atrial fibrillation (AF) patients was shown to contribute to atrial action potential duration shortening, a key feature of AF-associated atrial electrical remodelling. Therefore, targeting K2P3.1 (TASK-1) channels might constitute an intriguing strategy for AF treatment. Further, mechanoactive K2P2.1 (TREK-1) currents have been implicated in the development of cardiac hypertrophy, cardiac fibrosis and heart failure. Cardiovascular expression of other K2P channels has been described, functional evidence in cardiac tissue however remains sparse. In the present review, expression, function, and regulation of cardiovascular K2P channels are summarized and compared among different species. Remodelling patterns, observed in disease models are discussed and compared to findings from clinical patients to assess the therapeutic potential of K2P channels.

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Muller-Delp, J. M. "The role of TREK-1 in cerebrovascular regulation remains elusive: focus on “Cerebrovascular responses in mice deficient in the potassium channel, TREK-1”." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 299, no. 2 (August 2010): R459—R460. http://dx.doi.org/10.1152/ajpregu.00277.2010.

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Fang, Yongkang, Xiaojiang Huang, Yue Wan, Hao Tian, Yeye Tian, Wei Wang, Suiqiang Zhu, and Minjie Xie. "Deficiency of TREK-1 potassium channel exacerbates secondary injury following spinal cord injury in mice." Journal of Neurochemistry 141, no. 2 (March 15, 2017): 236–46. http://dx.doi.org/10.1111/jnc.13980.

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Yin, Zongzhi, Yun Li, Wenzhu He, Dan Li, Hongyan Li, Yuanyuan Yang, Bing Shen, Xi Wang, Yunxia Cao, and Raouf A. Khalil. "Progesterone inhibits contraction and increases TREK-1 potassium channel expression in late pregnant rat uterus." Oncotarget 9, no. 1 (December 7, 2017): 651–61. http://dx.doi.org/10.18632/oncotarget.23084.

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44

Sharma, Pankaj, Stephen Hughes, Alicia El Haj, and Nicola Maffulli. "Expression of the Two Pore Domain Potassium Channel TREK-1 in Human Intervertebral Disc Cells." Current Stem Cell Research & Therapy 7, no. 4 (May 1, 2012): 266–71. http://dx.doi.org/10.2174/157488812800793072.

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Maingret, François, Amanda J. Patel, Florian Lesage, Michel Lazdunski, and Eric Honoré. "Mechano- or Acid Stimulation, Two Interactive Modes of Activation of the TREK-1 Potassium Channel." Journal of Biological Chemistry 274, no. 38 (September 17, 1999): 26691–96. http://dx.doi.org/10.1074/jbc.274.38.26691.

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Schwingshackl, Andreas, Bin Teng, Patrudu Makena, Manik Ghosh, Scott E. Sinclair, Charlean Luellen, Louisa Balasz, et al. "Deficiency of the Two-Pore-Domain Potassium Channel TREK-1 Promotes Hyperoxia-Induced Lung Injury." Critical Care Medicine 42, no. 11 (November 2014): e692-e701. http://dx.doi.org/10.1097/ccm.0000000000000603.

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Stebe, Sabrina, Katharina Schellig, Florian Lesage, Heinz Breer, and Joerg Fleischer. "The Thermosensitive Potassium Channel TREK-1 Contributes to Coolness-Evoked Responses of Grueneberg Ganglion Neurons." Cellular and Molecular Neurobiology 34, no. 1 (October 8, 2013): 113–22. http://dx.doi.org/10.1007/s10571-013-9992-x.

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Meadows, H. J., C. D. Benham, W. Cairns, I. Gloger, C. Jennings, A. D. Medhurst, P. Murdock, and C. G. Chapman. "Cloning, localisation and functional expression of the human orthologue of the TREK-1 potassium channel." Pfl�gers Archiv European Journal of Physiology 439, no. 6 (March 23, 2000): 714–22. http://dx.doi.org/10.1007/s004240050997.

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Meadows, H. J., C. D. Benham, W. Cairns, I. Gloger, C. Jennings, A. D. Medhurst, P. Murdock, and C. G. Chapman. "Cloning, localisation and functional expression of the human orthologue of the TREK-1 potassium channel." Pflügers Archiv - European Journal of Physiology 439, no. 6 (January 24, 2000): 714–22. http://dx.doi.org/10.1007/s004249900235.

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Rinné, Susanne, Vijay Renigunta, Günter Schlichthörl, Marylou Zuzarte, Stefan Bittner, Sven G. Meuth, Niels Decher, Jürgen Daut, and Regina Preisig-Müller. "A splice variant of the two-pore domain potassium channel TREK-1 with only one pore domain reduces the surface expression of full-length TREK-1 channels." Pflügers Archiv - European Journal of Physiology 466, no. 8 (November 7, 2013): 1559–70. http://dx.doi.org/10.1007/s00424-013-1384-z.

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