Journal articles: 'Tandem Pore Domain'

1

Yost, C. "Update on Tandem Pore (2P) Domain K+ Channels." Current Drug Targets 4, no. 4 (May 1, 2003): 347–51. http://dx.doi.org/10.2174/1389450033491091.

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Kindler, Christoph H., Spencer C. Yost, and Andrew T. Gray. "Local Anesthetic Inhibition of Baseline Potassium Channels with Two Pore Domains in Tandem." Anesthesiology 90, no. 4 (April 1, 1999): 1092–102. http://dx.doi.org/10.1097/00000542-199904000-00024.

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Background Recently, a new structural family of potassium channels characterized by two pore domains in tandem within their primary amino acid sequence was identified. These tandem pore domain potassium channels are not gated by voltage and appear to be involved in the control of baseline membrane conductances. The goal of this study was to identify mechanisms of local anesthetic action on these channels. Methods Oocytes of Xenopus laevis were injected with cRNA from five cloned tandem pore domain baseline potassium channels (TASK, TREK-1, TOK1, ORK1, and TWIK-1), and the effects of several local anesthetics on the heterologously expressed channels were assayed using two-electrode voltage-clamp and current-clamp techniques. Results Bupivacaine (1 mM) inhibited all studied tandem pore potassium channels, with TASK inhibited most potently. The potency of inhibition was directly correlated with the octanol: buffer distribution coefficient of the local anesthetic, with the exception of tetracaine, to which TASK is relatively insensitive. The approximate 50% inhibitory concentrations of TASK were 709 microM mepivacaine, 222 microM lidocaine, 51 microM R(+)-ropivacaine, 53 microM S(-)-ropivacaine, 668 microM tetracaine, 41 microM bupivacaine, and 39 microM etidocaine. Local anesthetics (1 mM) significantly depolarized the resting membrane potential of TASK cRNA-injected oocytes compared with saline-injected control oocytes (tetracaine 22+/-6 mV rs. 7+/-1 mV, respectively, and bupivacaine 31+/-7 mV vs. 6+/-4 mV). Conclusions Local anesthetics inhibit tandem pore domain baseline potassium channels, and they could depolarize the resting membrane potential of cells expressing these channels. Whether inhibition of these channels contributes to conduction blockade or to the adverse effects of local anesthetics remains to be determined.

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Rajan, Sindhu, Erhard Wischmeyer, Gong Xin Liu, Regina Preisig-Müller, Jürgen Daut, Andreas Karschin, and Christian Derst. "TASK-3, a Novel Tandem Pore Domain Acid-sensitive K+Channel." Journal of Biological Chemistry 275, no. 22 (March 27, 2000): 16650–57. http://dx.doi.org/10.1074/jbc.m000030200.

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Gray, Andrew T., Byron B. Zhao, Christoph H. Kindler, Bruce D. Winegar, Matthew J. Mazurek, Jie Xu, Raymond A. Chavez, John R. Forsayeth, and C. Spencer Yost. "Volatile Anesthetics Activate the Human Tandem Pore Domain Baseline K+Channel KCNK5." Anesthesiology 92, no. 6 (June 1, 2000): 1722–30. http://dx.doi.org/10.1097/00000542-200006000-00032.

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Background Previous studies have identified a volatile anesthetic-induced increase in baseline potassium permeability and concomitant neuronal inhibition. The emerging family of tandem pore domain potassium channels seems to function as baseline potassium channels in vivo. Therefore, we studied the effects of clinically used volatile anesthetics on a recently described member of this family. Methods A cDNA clone containing the coding sequence of KCNK5 was isolated from a human brain library. Expression of KCNK5 in the central nervous system was determined by Northern blot analysis and reverse-transcription polymerase chain reaction. Functional expression of the channel was achieved by injection of cRNA into Xenopus laevis oocytes. Results Expression of KCNK5 was detected in cerebral cortex, medulla, and spinal cord. When heterologously expressed in Xenopus oocytes, KCNK5 currents exhibited delayed activation, outward rectification, proton sensitivity, and modulation by protein kinase C. Clinical concentrations of volatile general anesthetics potentiated KCNK5 currents by 8-30%. Conclusion Human KCNK5 is a tandem pore domain potassium channel exhibiting delayed activation and sensitivity to volatile anesthetics and may therefore have a role in suppressing cellular excitability during general anesthesia.

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Yost, C. "Tandem Pore Domain K Channels An Important Site of Volatile Anesthetic Action." Current Drug Targets 1, no. 2 (September 1, 2000): 207–17. http://dx.doi.org/10.2174/1389450003349335.

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Bina, Robert Wagner, and Steven C. Hempleman. "Evidence for TREK-like tandem-pore domain channels in intrapulmonary chemoreceptor chemotransduction." Respiratory Physiology & Neurobiology 156, no. 2 (May 2007): 120–31. http://dx.doi.org/10.1016/j.resp.2006.09.005.

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Kananura, Colette, Thomas Sander, Sindhu Rajan, Regina Preisig-Müller, Karl-Heinz Grzeschik, Jürgen Daut, Christian Derst, and Ortrud K. Steinlein. "Tandem pore domain K+-channel TASK-3 (KCNK9) and idiopathic absence epilepsies." American Journal of Medical Genetics 114, no. 2 (January 9, 2002): 227–29. http://dx.doi.org/10.1002/ajmg.10201.

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8

Johnson, Rosalyn P., Ita M. O'Kelly, and Ian M. Fearon. "System-specific O2 sensitivity of the tandem pore domain K+ channel TASK-1." American Journal of Physiology-Cell Physiology 286, no. 2 (February 2004): C391—C397. http://dx.doi.org/10.1152/ajpcell.00401.2003.

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Hypoxic inhibition of TASK-1, a tandem pore domain background K+ channel, provides a critical link between reduced O2 levels and physiological responses in various cell types. Here, we examined the expression and O2 sensitivity of TASK-1 in immortalized adrenomedullary chromaffin (MAH) cells. In physiological (asymmetrical) K+ solutions, 3 μM anandamide or 300 μM Zn2+ inhibited a strongly pH-sensitive current. Under symmetrical K+ conditions, the anandamide- and Zn2+-sensitive K+ currents were voltage independent. These data demonstrate the functional expression of TASK-1, and cellular expression of this channel was confirmed by RT-PCR and Western blotting. At concentrations that selectively inhibit TASK-1, anandamide and Zn2+ were without effect on the magnitude of the O2-sensitive current or the hypoxic depolarization. Thus TASK-1 does not contribute to O2 sensing in MAH cells, demonstrating the failure of a known O2-sensitive K+ channel to respond to hypoxia in an O2-sensing cell. These data demonstrate that, ultimately, the sensitivity of a particular K+ channel to hypoxia is determined by the cell, and we propose that this is achieved by coupling distinct hypoxia signaling systems to individual channels. Importantly, these data also reiterate the indirect O2 sensitivity of TASK-1, which appears to require the presence of an intracellular mediator.

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Skatchkov, S. N., M. J. Eaton, Y. M. Shuba, Y. V. Kucheryavykh, C. Derst, R. W. Veh, A. Wurm, et al. "Tandem-pore domain potassium channels are functionally expressed in retinal (Müller) glial cells." Glia 53, no. 3 (2005): 266–76. http://dx.doi.org/10.1002/glia.20280.

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10

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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11

Rajan, Sindhu, Erhard Wischmeyer, Christine Karschin, Regina Preisig-Müller, Karl-Heinz Grzeschik, Jürgen Daut, Andreas Karschin, and Christian Derst. "THIK-1 and THIK-2, a Novel Subfamily of Tandem Pore Domain K+Channels." Journal of Biological Chemistry 276, no. 10 (November 1, 2000): 7302–11. http://dx.doi.org/10.1074/jbc.m008985200.

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Hur, C. G., D. Kang, J. Y. Park, S. G. Hong, and J. Han. "269 EXPRESSION OF TANDEM-PORE DOMAIN K+ CHANNELS IN BOVINE OOCYTES AND PRE-IMPLANTATION EMBRYOS." Reproduction, Fertility and Development 19, no. 1 (2007): 251. http://dx.doi.org/10.1071/rdv19n1ab269.

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Tandem-pore domain K+ (K2P) channels that contribute to setting the resting membrane potential of excitable and nonexcitable cells are expressed in many kinds of cells and tissues. Recent studies have shown that TASK [TWIK (Tandem of P domains in Weak Inward rectifying K+ channels)-related acid-sensitive K+ channels] and TREK (TWIK-Related K+ channels), members of K2P channel family that are involved in a variety of cellular functions, are expressed in human myometrium, placenta, and cytotrophoblast cells. However, their expression in bovine oocytes and embryos has not yet been reported. In this study, we examined whether TASK and TREK channels are expressed in bovine immature (germinal vesicle-stage) and mature (metaphase II-stage) oocytes and in pre-implantation (2-cell- and 16-cell-stage) embryos using RT-PCR and immunocytochemistry. RT-PCR data showed that TASK-1, TASK-3, TREK-1, TREK-2, and TRAAK channels were expressed in bovine immature and mature oocytes. Interestingly, the expression levels of TREK channels were 2-fold higher than those of TASK channels as judged by semiquantitative RT-PCR and real-time PCR with cDNA synthesized from 50 individual immature and mature oocytes (P < 0.05, n = 4). Intensity of genes was normalized with respect to that of GAPDH. Consistent with RT-PCR data, immunocytochemical data showed that TASK-1, TASK-3, TREK-1, TREK-2, and TRAAK channels were expressed in bovine immature and mature oocytes. The fluorescence intensity of TREK channels was higher than that of TASK channels (P < 0.05, n = 5). TASK and TREK channels were also expressed in pre-implantation embryos. Of TREK channels, the TREK-2 channel was strongly expressed in immature and mature oocytes and in pre-implantation embryos (P < 0.05, n = 5). For statistics, Student's t-test was used, with P < 0.05 as the criterion for significance. Our results show that TASK-1, TASK-3, TREK-1, TREK-2, and TRAAK channels were expressed in bovine immature and mature oocytes and pre-implantation embryos. These results suggest that TASK and TREK channels could be involved in various physiological processes in mammalian oocytes and embryos.

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13

Prunuske, Amy J., Jin Liu, Suzanne Elgort, Jomon Joseph, Mary Dasso, and Katharine S. Ullman. "Nuclear Envelope Breakdown Is Coordinated by Both Nup358/RanBP2 and Nup153, Two Nucleoporins with Zinc Finger Modules." Molecular Biology of the Cell 17, no. 2 (February 2006): 760–69. http://dx.doi.org/10.1091/mbc.e05-06-0485.

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When higher eukaryotic cells transition into mitosis, the nuclear envelope, nuclear pore complexes, and nuclear lamina are coordinately disassembled. The COPI coatomer complex, which plays a major role in membrane remodeling at the Golgi, has been implicated in the process of nuclear envelope breakdown and requires interactions at the nuclear pore complex for recruitment to this new site of action at mitosis. Nup153, a resident of the nuclear pore basket, was found to be involved in COPI recruitment, but the molecular nature of the interface between COPI and the nuclear pore has not been fully elucidated. To better understand what occurs at the nuclear pore at this juncture, we have probed the role of the nucleoporin Nup358/RanBP2. Nup358 contains a repetitive zinc finger domain with overall organization similar to a region within Nup153 that is critical to COPI association, yet inspection of these two zinc finger domains reveals features that also clearly distinguish them. Here, we found that the Nup358 zinc finger domain, but not a zinc finger domain from an unrelated protein, binds to COPI and dominantly inhibits progression of nuclear envelope breakdown in an assay that robustly recapitulates this process in vitro. Moreover, the Nup358 zinc finger domain interferes with COPI recruitment to the nuclear rim. Consistent with a role for this pore protein in coordinating nuclear envelope breakdown, Nup358-specific antibodies impair nuclear disassembly. Significantly, targeting either Nup153 or Nup358 for inhibition perturbs nuclear envelope breakdown, supporting a model in which these nucleoporins play nonredundant roles, perhaps contributing to COPI recruitment platforms on both the nuclear and cytoplasmic faces of the pore. We found that an individual zinc finger is the minimal interface for COPI association, although tandem zinc fingers are optimal. These results provide new information about the critical components of nuclear membrane remodeling and lay the foundation for a better understanding of how this process is regulated.

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Rouaud, Florian, Francesca Tessaro, Laura Aimaretti, Leonardo Scapozza, and Sandra Citi. "Cooperative binding of the tandem WW domains of PLEKHA7 to PDZD11 promotes conformation-dependent interaction with tetraspanin 33." Journal of Biological Chemistry 295, no. 28 (May 5, 2020): 9299–312. http://dx.doi.org/10.1074/jbc.ra120.012987.

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Pleckstrin homology domain–containing A7 (PLEKHA7) is a cytoplasmic protein at adherens junctions that has been implicated in hypertension, glaucoma, and responses to Staphylococcus aureus α-toxin. Complex formation between PLEKHA7, PDZ domain–containing 11 (PDZD11), tetraspanin 33, and the α-toxin receptor ADAM metallopeptidase domain 10 (ADAM10) promotes junctional clustering of ADAM10 and α-toxin–mediated pore formation. However, how the N-terminal region of PDZD11 interacts with the N-terminal tandem WW domains of PLEKHA7 and how this interaction promotes tetraspanin 33 binding to the WW1 domain is unclear. Here, we used site-directed mutagenesis, glutathione S-transferase pulldown experiments, immunofluorescence, molecular modeling, and docking experiments to characterize the mechanisms driving these interactions. We found that Asp-30 of WW1 and His-75 of WW2 interact through a hydrogen bond and, together with Thr-35 of WW1, form a binding pocket that accommodates a polyproline stretch within the N-terminal PDZD11 region. By strengthening the interactions of the ternary complex, the WW2 domain stabilized the WW1 domain and cooperatively promoted the interaction with PDZD11. Modeling results indicated that, in turn, PDZD11 binding induces a conformational rearrangement, which strengthens the ternary complex, and contributes to enlarging a “hydrophobic hot spot” region on the WW1 domain. The last two lipophilic residues of tetraspanin 33, Trp-283 and Tyr-282, were required for its interaction with PLEKHA7. Docking of the tetraspanin 33 C terminus revealed that it fits into the hydrophobic hot spot region of the accessible surface of WW1. We conclude that communication between the two tandem WW domains of PLEKHA7 and the PLEKHA7–PDZD11 interaction modulate the ligand-binding properties of PLEKHA7.

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Ambort, Daniel, Sjoerd van der Post, Malin E. V. Johansson, Jenny MacKenzie, Elisabeth Thomsson, Ute Krengel, and Gunnar C. Hansson. "Function of the CysD domain of the gel-forming MUC2 mucin." Biochemical Journal 436, no. 1 (April 27, 2011): 61–70. http://dx.doi.org/10.1042/bj20102066.

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The colonic human MUC2 mucin forms a polymeric gel by covalent disulfide bonds in its N- and C-termini. The middle part of MUC2 is largely composed of two highly O-glycosylated mucin domains that are interrupted by a CysD domain of unknown function. We studied its function as recombinant proteins fused to a removable immunoglobulin Fc domain. Analysis of affinity-purified fusion proteins by native gel electrophoresis and gel filtration showed that they formed oligomeric complexes. Analysis of the individual isolated CysD parts showed that they formed dimers both when flanked by two MUC2 tandem repeats and without these. Cleavages of the two non-reduced CysD fusion proteins and analysis by MS revealed the localization of all five CysD disulfide bonds and that the predicted C-mannosylated site was not glycosylated. All disulfide bonds were within individual peptides showing that the domain was stabilized by intramolecular disulfide bonds and that CysD dimers were of non-covalent nature. These observations suggest that CysD domains act as non-covalent cross-links in the MUC2 gel, thereby determining the pore sizes of the mucus.

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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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Chavez, Raymond A., Andrew T. Gray, Byron B. Zhao, Christoph H. Kindler, Matthew J. Mazurek, Yash Mehta, John R. Forsayeth, and C. Spencer Yost. "TWIK-2, a new weak inward rectifying member of the tandem pore domain potassium channel family." Journal of Biological Chemistry 274, no. 34 (August 1999): 24440. http://dx.doi.org/10.1016/s0021-9258(19)55579-x.

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18

Kindler, Christoph H., Christian Pietruck, C. Spencer Yost, Elizabeth R. Sampson, and Andrew T. Gray. "Localization of the tandem pore domain K+ channel TASK-1 in the rat central nervous system." Molecular Brain Research 80, no. 1 (July 2000): 99–108. http://dx.doi.org/10.1016/s0169-328x(00)00136-4.

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19

Blin, Sandy, Franck C. Chatelain, Sylvain Feliciangeli, Dawon Kang, Florian Lesage, and Delphine Bichet. "Tandem Pore Domain Halothane-inhibited K+Channel Subunits THIK1 and THIK2 Assemble and Form Active Channels." Journal of Biological Chemistry 289, no. 41 (August 22, 2014): 28202–12. http://dx.doi.org/10.1074/jbc.m114.600437.

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20

Chavez, Raymond A., Andrew T. Gray, Byron B. Zhao, Christoph H. Kindler, Matthew J. Mazurek, Yash Mehta, John R. Forsayeth, and C. Spencer Yost. "TWIK-2, a New Weak Inward Rectifying Member of the Tandem Pore Domain Potassium Channel Family." Journal of Biological Chemistry 274, no. 12 (March 19, 1999): 7887–92. http://dx.doi.org/10.1074/jbc.274.12.7887.

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21

Kindler, Christoph H., Matthias Paul, Hilary Zou, Canhui Liu, Bruce D. Winegar, Andrew T. Gray, and C. Spencer Yost. "Amide Local Anesthetics Potently Inhibit the Human Tandem Pore Domain Background K+ Channel TASK-2 (KCNK5)." Journal of Pharmacology and Experimental Therapeutics 306, no. 1 (March 26, 2003): 84–92. http://dx.doi.org/10.1124/jpet.103.049809.

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22

Braun, Isabelle C., Andrea Herold, Michaela Rode, and Elisa Izaurralde. "Nuclear Export of mRNA by TAP/NXF1 Requires Two Nucleoporin-Binding Sites but Not p15." Molecular and Cellular Biology 22, no. 15 (August 1, 2002): 5405–18. http://dx.doi.org/10.1128/mcb.22.15.5405-5418.2002.

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ABSTRACT Metazoan NXF1/p15 heterodimers promote export of bulk mRNA through nuclear pore complexes (NPC). NXF1 interacts with the NPC via two distinct structural domains, the UBA-like domain and the NTF2-like scaffold, which results from the heterodimerization of the NTF2-like domain of NXF1 with p15. Both domains feature a single nucleoporin-binding site, and they act synergistically to promote NPC translocation. Whether the NTF2-like scaffold (and thereby p15) contributes only to NXF1/NPC association or is also required for other functions, e.g., to impart directionality to the export process by regulating NXF1/NPC or NXF1/cargo interactions, remains unresolved. Here we show that a minimum of two nucleoporin-binding sites is required for NXF1-mediated export of cellular mRNA. These binding sites can be provided by an NTF2-like scaffold followed by a UBA-like domain (as in the wild-type protein) or by two NTF2-like scaffolds or two UBA-like domains in tandem. In the latter case, the export activity of NXF1 is independent of p15. Thus, as for the UBA-like domain, the function of the NTF2-like scaffold is confined to nucleoporin binding. More importantly, two copies of either of these domains are sufficient to promote directional transport of mRNA cargoes across the NPC.

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Lengyel, Miklós, Gábor Czirják, David A. Jacobson, and Péter Enyedi. "TRESK and TREK-2 two-pore-domain potassium channel subunits form functional heterodimers in primary somatosensory neurons." Journal of Biological Chemistry 295, no. 35 (July 7, 2020): 12408–25. http://dx.doi.org/10.1074/jbc.ra120.014125.

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Two-pore-domain potassium channels (K2P) are the major determinants of the background potassium conductance. They play a crucial role in setting the resting membrane potential and regulating cellular excitability. These channels form homodimers; however, a few examples of heterodimerization have also been reported. The K2P channel subunits TRESK and TREK-2 provide the predominant background potassium current in the primary sensory neurons of the dorsal root and trigeminal ganglia. A recent study has shown that a TRESK mutation causes migraine because it leads to the formation of a dominant negative truncated TRESK fragment. Surprisingly, this fragment can also interact with TREK-2. In this study, we determined the biophysical and pharmacological properties of the TRESK/TREK-2 heterodimer using a covalently linked TRESK/TREK-2 construct to ensure the assembly of the different subunits. The tandem channel has an intermediate single-channel conductance compared with the TRESK and TREK-2 homodimers. Similar conductance values were recorded when TRESK and TREK-2 were coexpressed, demonstrating that the two subunits can spontaneously form functional heterodimers. The TRESK component confers calcineurin-dependent regulation to the heterodimer and gives rise to a pharmacological profile similar to the TRESK homodimer, whereas the presence of the TREK-2 subunit renders the channel sensitive to the selective TREK-2 activator T2A3. In trigeminal primary sensory neurons, we detected single-channel activity with biophysical and pharmacological properties similar to the TRESK/TREK-2 tandem, indicating that WT TRESK and TREK-2 subunits coassemble to form functional heterodimeric channels also in native cells.

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Gabriel, Anja, Mona Abdallah, C. Spencer Yost, Bruce D. Winegar, and Christoph H. Kindler. "Localization of the tandem pore domain K+ channel KCNK5 (TASK-2) in the rat central nervous system." Molecular Brain Research 98, no. 1-2 (January 2002): 153–63. http://dx.doi.org/10.1016/s0169-328x(01)00330-8.

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Li, Zheng-Bin, Hai-Xia Zhang, Liao-Liao Li, and Xiao-Liang Wang. "Enhanced expressions of arachidonic acid-sensitive tandem-pore domain potassium channels in rat experimental acute cerebral ischemia." Biochemical and Biophysical Research Communications 327, no. 4 (February 2005): 1163–69. http://dx.doi.org/10.1016/j.bbrc.2004.12.124.

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Mah, Nancy, Carolina Perez-Iratxeta, and Miguel A. Andrade-Navarro. "Outer membrane pore protein prediction in mycobacteria using genomic comparison." Microbiology 156, no. 8 (August 1, 2010): 2506–15. http://dx.doi.org/10.1099/mic.0.040089-0.

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Proteins responsible for outer membrane transport across the unique membrane structure of Mycobacterium spp. are attractive drug targets in the treatment of human diseases caused by the mycobacterial pathogens, Mycobacterium tuberculosis, M. bovis, M. leprae and M. ulcerans. In contrast with Escherichia coli, relatively few outer-membrane proteins (OMPs) have been identified in Mycobacterium spp., largely due to the difficulties in isolating mycobacterial membrane proteins and our incomplete understanding of secretion mechanisms and cell wall structure in these organisms. To further expand our knowledge of these elusive proteins in mycobacteria, we have improved upon our previous method of OMP prediction in mycobacteria by taking advantage of genomic data from seven mycobacteria species. Our improved algorithm suggests 4333 sequences as putative OMPs in seven species with varying degrees of confidence. The most virulent pathogenic mycobacterial species are slightly enriched in these selected sequences. We present examples of predicted OMPs involved in horizontal transfer and paralogy expansion. Analysis of local secondary structure content allowed identification of small domains predicted to perform as OMPs; some examples show their involvement in events of tandem duplication and domain rearrangements. We discuss the taxonomic distribution of these discovered families and architectures, often specific to mycobacteria or the wider taxonomic class of Actinobacteria. Our results suggest that OMP functionality in mycobacteria is richer than expected and provide a resource to guide future research of these understudied proteins.

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Smith, Howard. "Calcineurin as a Nociceptor Modulator." Pain Physician 4;12, no. 4;7 (July 14, 2009): E309—E318. http://dx.doi.org/10.36076/ppj.2009/12/e09.

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Calcineurin may be involved in affecting nociceptive processes in multiple circumstances. It is conceivable that interfering with calcineurin’s normal role in contributing to glial resting membrane potential, via its effects on the ion channel (TRESK) [tandem-pore-domain weakly inward rectifying potassium channels (TWIK)-related spinal cord potassium channels] may facilitate nociception. Another aspect of calcineurin function may be its role in the pronociceptive signaling of nuclear factor of activated T-cells (NFAT). NFAT activation via mediators (e.g. Substance P, brain-derived neurotrophic factor, nerve growth factor, bradykinin) appears to be dependent on calcineurin function. This calcineurin-regulated NFAT signaling may subsequently lead to transcription of pronociceptive genes as well as upregulation of pronociceptive chemokine receptors in the dorsal root ganglion. In fact, multiple articles have described the clinical use of calcineurin-inhibitors leading to pain, a phenomenon referred to as calcineurin inhibitor-induced pain syndrome (CIPS). Thus, it appears that calcineurin functions may encompass actions which promote or dampen nociceptive processes. A greater understanding of the physiology of calcineurin, especially as it relates to modulating nociception may lead to the development of novel analgesic targets in attempts to optimally alleviate patient discomfort. Key words: Pain, neuropathic, calcineurin, NFAT, TRESK-[Tandem-pore-domain weakly inward rectifying potassium channels (TWIK)-related spinal cord potassium channels], CIPS (calcineurin-induced pain syndrome)

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Meadows, H. J., C. G. Chapman, D. M. Duckworth, R. E. Kelsell, P. R. Murdock, S. Nasir, G. Rennie, and A. D. Randall. "The neuroprotective agent sipatrigine (BW619C89) potently inhibits the human tandem pore-domain K+ channels TREK-1 and TRAAK." Brain Research 892, no. 1 (February 2001): 94–101. http://dx.doi.org/10.1016/s0006-8993(00)03239-x.

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Bertaccini, Edward J., Robert Dickinson, James R. Trudell, and Nicholas P. Franks. "Molecular Modeling of a Tandem Two Pore Domain Potassium Channel Reveals a Putative Binding Site for General Anesthetics." ACS Chemical Neuroscience 5, no. 12 (October 31, 2014): 1246–52. http://dx.doi.org/10.1021/cn500172e.

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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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Mazzolini, Monica, Claudio Anselmi, and Vincent Torre. "The analysis of desensitizing CNGA1 channels reveals molecular interactions essential for normal gating." Journal of General Physiology 133, no. 4 (March 16, 2009): 375–86. http://dx.doi.org/10.1085/jgp.200810157.

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The pore region of cyclic nucleotide–gated (CNG) channels acts as the channel gate. Therefore, events occurring in the cyclic nucleotide–binding (CNB) domain must be coupled to the movements of the pore walls. When Glu363 in the pore region, Leu356 and Thr355 in the P helix, and Phe380 in the upper portion of the S6 helix are mutated into an alanine, gating is impaired: mutant channels E363A, L356A, T355A, and F380A desensitize in the presence of a constant cGMP concentration, contrary to what can be observed in wild-type (WT) CNGA1 channels. Similarly to C-type inactivation of K+ channels, desensitization in these mutant channels is associated with rearrangements of residues in the outer vestibule. In the desensitized state, Thr364 residues in different subunits become closer and Pro366 becomes more accessible to extracellular reagents. Desensitization is also observed in the mutant channel L356C, but not in the double-mutant channel L356C+F380C. Mutant channels L356F and F380K did not express, but cGMP-gated currents with a normal gating were observed in the double-mutant channels L356F+F380L and L356D+F380K. Experiments with tandem constructs with L356C, F380C, and L356C+F380C and WT channels indicate that the interaction between Leu356 and Phe380 is within the same subunit. These results show that Leu356 forms a hydrophobic interaction with Phe380, coupling the P helix with S6, whereas Glu363 could interact with Thr355, coupling the pore wall to the P helix. These interactions are essential for normal gating and underlie the transduction between the CNB domain and the pore.

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Wells, G. D., Q. Y. Tang, R. Heler, G. J. Tompkins-MacDonald, E. N. Pritchard, S. P. Leys, D. E. Logothetis, and L. M. Boland. "A unique alkaline pH-regulated and fatty acid-activated tandem pore domain potassium channel (K2P) from a marine sponge." Journal of Experimental Biology 215, no. 14 (June 20, 2012): 2435–44. http://dx.doi.org/10.1242/jeb.066233.

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Keceli, Batu, and Yoshihiro Kubo. "Signal transmission within the P2X2 trimeric receptor." Journal of General Physiology 143, no. 6 (May 26, 2014): 761–82. http://dx.doi.org/10.1085/jgp.201411166.

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P2X2 receptor channel, a homotrimer activated by the binding of extracellular adenosine triphosphate (ATP) to three intersubunit ATP-binding sites (each located ∼50 Å from the ion permeation pore), also shows voltage-dependent activation upon hyperpolarization. Here, we used tandem trimeric constructs (TTCs) harboring critical mutations at the ATP-binding, linker, and pore regions to investigate how the ATP activation signal is transmitted within the trimer and how signals generated by ATP and hyperpolarization converge. Analysis of voltage- and [ATP]-dependent gating in these TTCs showed that: (a) Voltage- and [ATP]-dependent gating of P2X2 requires binding of at least two ATP molecules. (b) D315A mutation in the β-14 strand of the linker region connecting the ATP-binding domains to the pore-forming helices induces two different gating modes; this requires the presence of the D315A mutation in at least two subunits. (c) The T339S mutation in the pore domains of all three subunits abolishes the voltage dependence of P2X2 gating in saturating [ATP], making P2X2 equally active at all membrane potentials. Increasing the number of T339S mutations in the TTC results in gradual changes in the voltage dependence of gating from that of the wild-type channel, suggesting equal and independent contributions of the subunits at the pore level. (d) Voltage- and [ATP]-dependent gating in TTCs differs depending on the location of one D315A relative to one K308A that blocks the ATP binding and downstream signal transmission. (e) Voltage- and [ATP]-dependent gating does not depend on where one T339S is located relative to K308A (or D315A). Our results suggest that each intersubunit ATP-binding signal is directly transmitted on the same subunit to the level of D315 via the domain that contributes K308 to the β-14 strand. The signal subsequently spreads equally to all three subunits at the level of the pore, resulting in symmetric and independent contributions of the three subunits to pore opening.

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Noto, Federico, Sandra Recuero, Julián Valencia, Beatrice Saporito, Domenico Robbe, Sergi Bonet, Augusto Carluccio, and Marc Yeste. "Inhibition of Potassium Channels Affects the Ability of Pig Spermatozoa to Elicit Capacitation and Trigger the Acrosome Exocytosis Induced by Progesterone." International Journal of Molecular Sciences 22, no. 4 (February 17, 2021): 1992. http://dx.doi.org/10.3390/ijms22041992.

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During capacitation, sperm undergo a myriad of changes, including remodeling of plasma membrane, modification of sperm motility and kinematic parameters, membrane hyperpolarization, increase in intracellular calcium levels, and tyrosine phosphorylation of certain sperm proteins. While potassium channels have been reported to be crucial for capacitation of mouse and human sperm, their role in pigs has not been investigated. With this purpose, sperm samples from 15 boars were incubated in capacitation medium for 300 min with quinine, a general blocker of potassium channels (including voltage-gated potassium channels, calcium-activated potassium channels, and tandem pore domain potassium channels), and paxilline (PAX), a specific inhibitor of calcium-activated potassium channels. In all samples, acrosome exocytosis was induced after 240 min of incubation with progesterone. Plasma membrane and acrosome integrity, membrane lipid disorder, intracellular calcium levels, mitochondrial membrane potential, and total and progressive sperm motility were evaluated after 0, 120, and 240 min of incubation, and after 5, 30, and 60 min of progesterone addition. Although blocking potassium channels with quinine and PAX prevented sperm to elicit in vitro capacitation by impairing motility and mitochondrial function, as well as reducing intracellular calcium levels, the extent of that inhibition was larger with quinine than with PAX. Therefore, while our data support that calcium-activated potassium channels are essential for sperm capacitation in pigs, they also suggest that other potassium channels, such as the voltage-gated, tandem pore domain, and mitochondrial ATP-regulated ones, are involved in that process. Thus, further research is needed to elucidate the specific functions of these channels and the mechanisms underlying its regulation during sperm capacitation.

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Han, Jaehee, Dawon Kang, and Donghee Kim. "Functional properties of four splice variants of a human pancreatic tandem-pore K+ channel, TALK-1." American Journal of Physiology-Cell Physiology 285, no. 3 (September 2003): C529—C538. http://dx.doi.org/10.1152/ajpcell.00601.2002.

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TALK-1a, originally isolated from human pancreas, is a member of the tandem-pore K+ channel family. We identified and characterized three novel splice variants of TALK-1 from human pancreas. The cDNAs of TALK-1b, TALK-1c, and TALK-1d encode putative proteins of 294, 322, and 262 amino acids, respectively. TALK-1a and TALK-1b possessed all four transmembrane segments, whereas TALK-1c and TALK-1d lacked the fourth transmembrane domain because of deletion of exon 5. Northern blot analysis showed that among the 15 tissues examined, TALK-1 was expressed mainly in the pancreas. TALK-1a and TALK-1b, but not TALK-1c and TALK-1d, could be functionally expressed in COS-7 cells. Like TALK-1a, TALK-1b was a K+-selective channel that was active at rest. Single-channel openings of TALK-1a and TALK-1b were extremely brief such that the mean open time was <0.2 ms. In symmetrical 150 mM KCl, the apparent single-channel conductances of TALK-1a and TALK-1b were 23 ± 3 and 21 ± 2 pS at –60 mV and 11 ± 2 and 10 ± 2 pS at +60 mV, respectively. TALK-1b whole cell current was inhibited 31% by 1 mM Ba2+ and 71% by 1 mM quinidine but was not affected by 1 mM tetraethylammonium, 1 mM Cs+, and 100 μM 4-aminopyridine. Similar to TALK-1a, TALK-1b was sensitive to changes in external pH. Acid conditions inhibited and alkaline conditions activated TALK-1a and TALK-1b, with a K1/2 at pH 7.16 and 7.21, respectively. These results indicate that at least two functional TALK-1 variants are present and may serve as background K+ currents in certain cells of the human pancreas.

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Nishizuka, Makoto, Takahiro Hayashi, Mami Asano, Shigehiro Osada, and Masayoshi Imagawa. "KCNK10, a Tandem Pore Domain Potassium Channel, Is a Regulator of Mitotic Clonal Expansion during the Early Stage of Adipocyte Differentiation." International Journal of Molecular Sciences 15, no. 12 (December 9, 2014): 22743–56. http://dx.doi.org/10.3390/ijms151222743.

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Peracchia, Camillo, Xiao G. Wang, and Lillian L. Peracchia. "Is the chemical gate of connexins voltage sensitive? Behavior of Cx32 wild-type and mutant channels." American Journal of Physiology-Cell Physiology 276, no. 6 (June 1, 1999): C1361—C1373. http://dx.doi.org/10.1152/ajpcell.1999.276.6.c1361.

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Connexin channels are gated by transjunctional voltage ( V j) or CO2 via distinct mechanisms. The cytoplasmic loop (CL) and arginines of a COOH-terminal domain (CT1) of connexin32 (Cx32) were shown to determine CO2sensitivity, and a gating mechanism involving CL-CT1 association-dissociation was proposed. This study reports that Cx32 mutants, tandem, 5R/E, and 5R/N, designed to weaken CL-CT1interactions, display atypical V jand CO2 sensitivities when tested heterotypically with Cx32 wild-type channels in Xenopus oocytes. In tandems, two Cx32 monomers are linked NH2-to-COOH terminus. In 5R/E and 5R/N mutants, glutamates or asparagines replace CT1 arginines. On the basis of the intriguing sensitivity of the mutant-32 channel to V jpolarity, the existence of a “slow gate” distinct from the conventional V jgate is proposed. To a lesser extent the slow gate manifests itself also in homotypic Cx32 channels. Mutant-32 channels are more CO2 sensitive than homotypic Cx32 channels, and CO2-induced chemical gating is reversed with relative depolarization of the mutant oocyte, suggesting V jsensitivity of chemical gating. A hypothetical pore-plugging model involving an acidic cytosolic protein (possibly calmodulin) is discussed.

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Chapman, Mark L., and Antonius M. J. VanDongen. "K Channel Subconductance Levels Result from Heteromeric Pore Conformations." Journal of General Physiology 126, no. 2 (July 25, 2005): 87–103. http://dx.doi.org/10.1085/jgp.200509253.

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Voltage-gated K channels assemble from four identical subunits symmetrically arranged around a central permeation pathway. Each subunit harbors a voltage-sensing domain. The sigmoidal nature of the activation kinetics suggests that multiple sensors need to undergo a conformational change before the channel can open. Following activation, individual K channels alternate stochastically between two main permeation states, open and closed. This binary character of single channel behavior suggests the presence of a structure in the permeation pathway that can exist in only two conformations. However, single channel analysis of drk1 (Kv2.1) K channels demonstrated the existence of four additional, intermediate conductance levels. These short-lived subconductance levels are visited when the channel gate moves between the closed and fully open state. We have proposed that these sublevels arise from transient heteromeric pore conformations, in which some, but not all, subunits are in the “open” state. A minimal model based on this hypothesis relates specific subconductance states with the number of activated subunits (Chapman et al., 1997). To stringently test this hypothesis, we constructed a tandem dimer that links two K channel subunits with different activation thresholds. Activation of this dimer by strong depolarizations resulted in the characteristic binary open–close behavior. However, depolarizations to membrane potentials in between the activation thresholds of the two parents elicited highly unusual single channel gating, displaying frequent visits to two subconductance levels. The voltage dependence and kinetics of the small and large sublevels associate them with the activation of one and two subunits, respectively. The data therefore support the hypothesis that subconductance levels result from heteromeric pore conformations. In this model, both sensor movement and channel opening have a subunit basis and these processes are allosterically coupled.

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Duan, Wei, Jonné Hicks, Michael A. Makara, Olga Ilkayeva, and Dennis M. Abraham. "TASK-1 and TASK-3 channels modulate pressure overload-induced cardiac remodeling and dysfunction." American Journal of Physiology-Heart and Circulatory Physiology 318, no. 3 (March 1, 2020): H566—H580. http://dx.doi.org/10.1152/ajpheart.00739.2018.

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Tandem pore domain acid-sensitive K+ (TASK) channels are present in cardiac tissue; however, their contribution to cardiac pathophysiology is not well understood. Here, we investigate the role of TASK-1 and TASK-3 in the pathogenesis of cardiac dysfunction using both human tissue and mouse models of genetic TASK channel loss of function. Compared with normal human cardiac tissue, TASK-1 gene expression is reduced in association with either cardiac hypertrophy alone or combined cardiac hypertrophy and heart failure. In a pressure overload cardiomyopathy model, TASK-1 global knockout (TASK-1 KO) mice have both reduced cardiac hypertrophy and preserved cardiac function compared with wild-type mice. In contrast to the TASK-1 KO mouse pressure overload response, TASK-3 global knockout (TASK-3 KO) mice develop cardiac hypertrophy and a delayed onset of cardiac dysfunction compared with wild-type mice. The cardioprotective effects observed in TASK-1 KO mice are associated with pressure overload-induced augmentation of AKT phosphorylation and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) expression, with consequent augmentation of cardiac energetics and fatty acid oxidation. The protective effects of TASK-1 loss of function are associated with an enhancement of physiologic hypertrophic signaling and preserved metabolic functions. These findings may provide a rationale for TASK-1 channel inhibition in the treatment of cardiac dysfunction. NEW & NOTEWORTHY The role of tandem pore domain acid-sensitive K+ (TASK) channels in cardiac function is not well understood. This study demonstrates that TASK channel gene expression is associated with the onset of human cardiac hypertrophy and heart failure. TASK-1 and TASK-3 strongly affect the development of pressure overload cardiomyopathies in genetic models of TASK-1 and TASK-3 loss of function. The effects of TASK-1 loss of function were associated with enhanced AKT phosphorylation and expression of peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1) transcription factor. These data suggest that TASK channels influence the development of cardiac hypertrophy and dysfunction in response to injury.

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Thakurta, Anjan G., William A. Whalen, Jin Ho Yoon, Anekella Bharathi, Libor Kozak, Craig Whiteford, Dona C. Love, John A. Hanover, and Ravi Dhar. "Crp79p, Like Mex67p, Is an Auxiliary mRNA Export Factor inSchizosaccharomyces pombe." Molecular Biology of the Cell 13, no. 8 (August 2002): 2571–84. http://dx.doi.org/10.1091/mbc.e01-11-0133.

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The export of mRNA from the nucleus to the cytoplasm involves interactions of proteins with mRNA and the nuclear pore complex. We isolated Crp79p, a novel mRNA export factor from the same synthetic lethal screen that led to the identification of spMex67p inSchizosaccharomyces pombe. Crp79p is a 710-amino-acid-long protein that contains three RNA recognition motif domains in tandem and a distinct C-terminus. Fused to green fluorescent protein (GFP), Crp79p localizes to the cytoplasm. Like Mex67p, Crp79-GFP binds poly(A)+ RNA in vivo, shuttles between the nucleus and the cytoplasm, and contains a nuclear export activity at the C-terminus that is Crm1p-independent. All of these properties are essential for Crp79p to promote mRNA export. Crp79p import into the nucleus depends on the Ran system. A domain of spMex67p previously identified as having a nuclear export activity can functionally substitute for the nuclear export activity at the C-terminus of Crp79p. Although both Crp79p and spMex67p function to export mRNA, Crp79p does not substitute for all of spMex67p functions and probably is not a functional homologue of spMex67p. We propose that Crp79p is a nonessential mRNA export carrier in S. pombe.

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Chatelain, Franck C., Delphine Bichet, Sylvain Feliciangeli, Marie-Madeleine Larroque, Véronique M. Braud, Dominique Douguet, and Florian Lesage. "Silencing of the Tandem Pore Domain Halothane-inhibited K+Channel 2 (THIK2) Relies on Combined Intracellular Retention and Low Intrinsic Activity at the Plasma Membrane." Journal of Biological Chemistry 288, no. 49 (October 25, 2013): 35081–92. http://dx.doi.org/10.1074/jbc.m113.503318.

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Karschin, Christine, Erhard Wischmeyer, Regina Preisig-Müller, Sindhu Rajan, Christian Derst, Karl-Heinz Grzeschik, Jürgen Daut, and Andreas Karschin. "Expression Pattern in Brain of TASK-1, TASK-3, and a Tandem Pore Domain K+ Channel Subunit, TASK-5, Associated with the Central Auditory Nervous System." Molecular and Cellular Neuroscience 18, no. 6 (December 2001): 632–48. http://dx.doi.org/10.1006/mcne.2001.1045.

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Ravens, Ursula. "Atrial-selective K+ channel blockers: potential antiarrhythmic drugs in atrial fibrillation?" Canadian Journal of Physiology and Pharmacology 95, no. 11 (November 2017): 1313–18. http://dx.doi.org/10.1139/cjpp-2017-0024.

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In the wake of demographic change in Western countries, atrial fibrillation has reached an epidemiological scale, yet current strategies for drug treatment of the arrhythmia lack sufficient efficacy and safety. In search of novel medications, atrial-selective drugs that specifically target atrial over other cardiac functions have been developed. Here, I will address drugs acting on potassium (K+) channels that are either predominantly expressed in atria or possess electrophysiological properties distinct in atria from ventricles. These channels include the ultra-rapidly activating, delayed outward-rectifying Kv1.5 channel conducting IKur, the acetylcholine-activated inward-rectifying Kir3.1/Kir3.4 channel conducting IK,ACh, the Ca2+-activated K+ channels of small conductance (SK) conducting ISK, and the two-pore domain K+ (K2P) channels (tandem of P domains, weak inward-rectifying K+ channels (TWIK-1), TWIK-related acid-sensitive K+ channels (TASK-1 and TASK-3)) that are responsible for voltage-independent background currents ITWIK-1, ITASK-1, and ITASK-3. Direct drug effects on these channels are described and their putative value in treatment of atrial fibrillation is discussed. Although many potential drug targets have emerged in the process of unravelling details of the pathophysiological mechanisms responsible for atrial fibrillation, we do not know whether novel antiarrhythmic drugs will be more successful when modulating many targets or a single specific one. The answer to this riddle can only be solved in a clinical context.

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Kim, Gyu-Tae, Adrian S. Siregar, Eun-Jin Kim, Eun-Shin Lee, Marie Merci Nyiramana, Min Seok Woo, Young-Sool Hah, Jaehee Han, and Dawon Kang. "Upregulation of TRESK Channels Contributes to Motor and Sensory Recovery after Spinal Cord Injury." International Journal of Molecular Sciences 21, no. 23 (November 26, 2020): 8997. http://dx.doi.org/10.3390/ijms21238997.

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TWIK (tandem-pore domain weak inward rectifying K+)-related spinal cord K+ channel (TRESK), a member of the two-pore domain K+ channel family, is abundantly expressed in dorsal root ganglion (DRG) neurons. It is well documented that TRESK expression is changed in several models of peripheral nerve injury, resulting in a shift in sensory neuron excitability. However, the role of TRESK in the model of spinal cord injury (SCI) has not been fully understood. This study investigates the role of TRESK in a thoracic spinal cord contusion model, and in transgenic mice overexpressed with the TRESK gene (TGTRESK). Immunostaining analysis showed that TRESK was expressed in the dorsal and ventral neurons of the spinal cord. The TRESK expression was increased by SCI in both dorsal and ventral neurons. TRESK mRNA expression was upregulated in the spinal cord and DRG isolated from the ninth thoracic (T9) spinal cord contusion rats. The expression was significantly upregulated in the spinal cord below the injury site at acute time points (6, 24, and 48 h) after SCI (p < 0.05). In addition, TRESK expression was markedly increased in DRGs below and adjacent to the injury site. TRESK was expressed in inflammatory cells. In addition, the number and fluorescence intensity of TRESK-positive neurons increased in the dorsal and ventral horns of the spinal cord after SCI. TGTRESK SCI mice showed faster paralysis recovery and higher mechanical threshold compared to wild-type (WT)-SCI mice. TGTRESK mice showed lower TNF-α concentrations in the blood than WT mice. In addition, IL-1β concentration and apoptotic signals in the caudal spinal cord and DRG were significantly decreased in TGTRESK SCI mice compared to WT-SCI mice (p < 0.05). These results indicate that TRESK upregulated following SCI contributes to the recovery of paralysis and mechanical pain threshold by suppressing the excitability of motor and sensory neurons and inflammatory and apoptotic processes.

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Rivas-Ramírez, Paula, Antonio Reboreda, Lola Rueda-Ruzafa, Salvador Herrera-Pérez, and J. Antonio Lamas. "PIP2 Mediated Inhibition of TREK Potassium Currents by Bradykinin in Mouse Sympathetic Neurons." International Journal of Molecular Sciences 21, no. 2 (January 8, 2020): 389. http://dx.doi.org/10.3390/ijms21020389.

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Bradykinin (BK), a hormone inducing pain and inflammation, is known to inhibit potassium M-currents (IM) and to increase the excitability of the superior cervical ganglion (SCG) neurons by activating the Ca2+-calmodulin pathway. M-current is also reduced by muscarinic agonists through the depletion of membrane phosphatidylinositol 4,5-biphosphate (PIP2). Similarly, the activation of muscarinic receptors inhibits the current through two-pore domain potassium channels (K2P) of the “Tandem of pore-domains in a Weakly Inward rectifying K+ channel (TWIK)-related channels” (TREK) subfamily by reducing PIP2 in mouse SCG neurons (mSCG). The aim of this work was to test and characterize the modulation of TREK channels by bradykinin. We used the perforated-patch technique to investigate riluzole (RIL) activated currents in voltage- and current-clamp experiments. RIL is a drug used in the palliative treatment of amyotrophic lateral sclerosis and, in addition to blocking voltage-dependent sodium channels, it also selectively activates the K2P channels of the TREK subfamily. A cell-attached patch-clamp was also used to investigate TREK-2 single channel currents. We report here that BK reduces spike frequency adaptation (SFA), inhibits the riluzole-activated current (IRIL), which flows mainly through TREK-2 channels, by about 45%, and reduces the open probability of identified single TREK-2 channels in cultured mSCG cells. The effect of BK on IRIL was precluded by the bradykinin receptor (B2R) antagonist HOE-140 (d-Arg-[Hyp3, Thi5, d-Tic7, Oic8]BK) but also by diC8PIP2 which prevents PIP2 depletion when phospholipase C (PLC) is activated. On the contrary, antagonizing inositol triphosphate receptors (IP3R) using 2-aminoethoxydiphenylborane (2-APB) or inhibiting protein kinase C (PKC) with bisindolylmaleimide did not affect the inhibition of IRIL by BK. In conclusion, bradykinin inhibits TREK-2 channels through the activation of B2Rs resulting in PIP2 depletion, much like we have demonstrated for muscarinic agonists. This mechanism implies that TREK channels must be relevant for the capture of information about pain and visceral inflammation.

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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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Gray, Andrew T., Bruce D. Winegar, Dmitri J. Leonoudakis, John R. Forsayeth, and Spencer C. Yost. "TOK1 Is a Volatile Anesthetic Stimulated K+Channel." Anesthesiology 88, no. 4 (April 1, 1998): 1076–84. http://dx.doi.org/10.1097/00000542-199804000-00029.

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Background Volatile anesthetic agents can activate the S channel, a baseline potassium (K+) channel, of the marine mollusk Aplysia. To investigate whether cloned ion channels with electrophysiologic properties similar to the S channel (potassium selectivity, outward rectification, and activation independent of voltage) also are modulated by volatile anesthetic agents, the authors expressed the cloned yeast ion channel TOK1 (tandem pore domain, outwardly rectifying K+ channel) in Xenopus oocytes and studied its sensitivity to volatile agents. Methods Standard two-electrode voltage and patch clamp recording methods were used to study TOK1 channels expressed in Xenopus oocytes. Results Studies with two-electrode voltage clamp at room temperature showed that halothane, isoflurane, and desflurane increased TOK1 outward currents by 48-65% in barium Frog Ringer's perfusate. The concentrations at which 50% potentiation occurred (EC50 values) were in the range of 768-814 microM (0.016-0.044 atm) and had a rank order of potency in atm in which halothane > isoflurane > desflurane. The potentiation of TOK1 by volatile anesthetic agents was rapid and reversible (onset and offset, 1-20 s). In contrast, the nonanesthetic 1,2-dichlorohexafluorocyclobutane did not potentiate TOK1 currents in concentrations up to five times the MAC value predicted by the Meyer-Overton hypothesis based on oil/gas partition coefficients. Single TOK1 channel currents were recorded from excised outside-out patches. The single channel open probability increased as much as twofold in the presence of isoflurane and rapidly returned to the baseline values on washout. Volatile anesthetic agents did not alter the TOK1 single channel current-voltage (I-V) relationship, however, suggesting that the site of action does not affect the permeation pathway of the channel. Conclusion TOK1 is a potassium channel that is stimulated by volatile anesthetic agents. The concentrations over which potentiation occurred (EC50 values) were higher than those commonly used in clinical practice (approximately twice MAC).

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Yuill, K. H., P. J. Stansfeld, I. Ashmole, M. J. Sutcliffe, and P. R. Stanfield. "The selectivity, voltage-dependence and acid sensitivity of the tandem pore potassium channel TASK-1: contributions of the pore domains." Pflügers Archiv - European Journal of Physiology 455, no. 2 (June 1, 2007): 333–48. http://dx.doi.org/10.1007/s00424-007-0282-7.

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Ketchum, Karen A., William J. Joiner, Andrew J. Sellers, Leonard K. Kaczmarek, and Steve A. N. Goldstein. "A new family of outwardly rectifying potassium channel proteins with two pore domains in tandem." Nature 376, no. 6542 (August 1995): 690–95. http://dx.doi.org/10.1038/376690a0.

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Leonoudakis, Dmitri, Andrew T. Gray, Bruce D. Winegar, Christoph H. Kindler, Masato Harada, Donald M. Taylor, Raymond A. Chavez, John R. Forsayeth, and C. Spencer Yost. "An Open Rectifier Potassium Channel with Two Pore Domains in Tandem Cloned from Rat Cerebellum." Journal of Neuroscience 18, no. 3 (February 1, 1998): 868–77. http://dx.doi.org/10.1523/jneurosci.18-03-00868.1998.

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Journal articles on the topic 'Tandem Pore Domain'

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