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Selective Small Molecule Activators of TREK-2 Channels Stimulate Dorsal Root Ganglion c-Fiber Nociceptor Two-Pore-Domain Potassium Channel Currents and Limit Calcium Influx.
Dadi PK, Vierra NC, Days E, Dickerson MT, Vinson PN, Weaver CD, Jacobson DA
(2017) ACS Chem Neurosci 8: 558-568
MeSH Terms: Action Potentials, Animals, Antibodies, Calcium, Dinoprostone, Electric Stimulation, Fluoxetine, Ganglia, Spinal, HEK293 Cells, Humans, Lectins, Mice, Mice, Inbred C57BL, Mutation, Nociceptors, Potassium Channel Blockers, Potassium Channels, Tandem Pore Domain, Protein Synthesis Inhibitors, Tetracycline
Show Abstract · Added November 13, 2017
The two-pore-domain potassium (K2P) channel TREK-2 serves to modulate plasma membrane potential in dorsal root ganglia c-fiber nociceptors, which tunes electrical excitability and nociception. Thus, TREK-2 channels are considered a potential therapeutic target for treating pain; however, there are currently no selective pharmacological tools for TREK-2 channels. Here we report the identification of the first TREK-2 selective activators using a high-throughput fluorescence-based thallium (Tl) flux screen (HTS). An initial pilot screen with a bioactive lipid library identified 11-deoxy prostaglandin F2α as a potent activator of TREK-2 channels (EC ≈ 0.294 μM), which was utilized to optimize the TREK-2 Tl flux assay (Z' = 0.752). A HTS was then performed with 76 575 structurally diverse small molecules. Many small molecules that selectively activate TREK-2 were discovered. As these molecules were able to activate single TREK-2 channels in excised membrane patches, they are likely direct TREK-2 activators. Furthermore, TREK-2 activators reduced primary dorsal root ganglion (DRG) c-fiber Ca influx. Interestingly, some of the selective TREK-2 activators such as 11-deoxy prostaglandin F2α were found to inhibit the K2P channel TREK-1. Utilizing chimeric channels containing portions of TREK-1 and TREK-2, the region of the TREK channels that allows for either small molecule activation or inhibition was identified. This region lies within the second pore domain containing extracellular loop and is predicted to play an important role in modulating TREK channel activity. Moreover, the selective TREK-2 activators identified in this HTS provide important tools for assessing human TREK-2 channel function and investigating their therapeutic potential for treating chronic pain.
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19 MeSH Terms
Quantifying heterogeneity and dynamics of clonal fitness in response to perturbation.
Frick PL, Paudel BB, Tyson DR, Quaranta V
(2015) J Cell Physiol 230: 1403-12
MeSH Terms: Cell Culture Techniques, Cell Line, Cell Proliferation, Clone Cells, Cycloheximide, Gene Expression Regulation, Genetic Fitness, Humans, Protein Synthesis Inhibitors
Show Abstract · Added February 19, 2015
The dynamics of heterogeneous clonal lineages within a cell population, in aggregate, shape both normal and pathological biological processes. Studies of clonality typically relate the fitness of clones to their relative abundance, thus requiring long-term experiments and limiting conclusions about the heterogeneity of clonal fitness in response to perturbation. We present, for the first time, a method that enables a dynamic, global picture of clonal fitness within a mammalian cell population. This novel assay allows facile comparison of the structure of clonal fitness in a cell population across many perturbations. By utilizing high-throughput imaging, our methodology provides ample statistical power to define clonal fitness dynamically and to visualize the structure of perturbation-induced clonal fitness within a cell population. We envision that this technique will be a powerful tool to investigate heterogeneity in biological processes involving cell proliferation, including development and drug response.
© 2015 Wiley Periodicals, Inc.
2 Communities
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9 MeSH Terms
Zeta inhibitory peptide (ZIP) erases long-term memories in a cockroach.
Deng Z, Lubinski AJ, Page TL
(2015) Neurobiol Learn Mem 118: 89-95
MeSH Terms: Animals, Benzophenanthridines, Carbazoles, Cockroaches, Conditioning (Psychology), Lipopeptides, Memory, Long-Term, Protein Kinase Inhibitors, Protein Synthesis Inhibitors, Pyrroles
Show Abstract · Added January 20, 2015
Recent efforts to identify the molecules that are involved in the maintenance of long-term memories in mammals have focused attention on atypical isoforms of protein kinase C (PKC). Inhibition of these kinases by either the general PKC inhibitor, chelerythrine, or the more specific inhibitor, zeta inhibitory peptide (ZIP), can abolish both long-term potentiation in the hippocampus and as well as spatial, fear, appetitive, and sensorimotor memories. These inhibitors can also abolish long-term facilitation and long-term sensitization in the mollusk Aplysia californica. We have extended these results to an insect, the cockroach Leucophaea maderae. We show that systemic injections of either chelerythrine or ZIP erase long-term olfactory memories in the cockroach, but have no effect on memory acquisition during conditioning. We also show that inhibition of either protein kinase A (PKA) or protein synthesis can block memory acquisition but neither has an effect on the memory once it is formed. The results suggest that sustaining memories in insects requires the persistent activity of one or more isoforms of PKC and point to a strong evolutionary conservation of the molecular mechanisms that underlie the persistence of long-term memories in the central nervous system.
Copyright © 2014 Elsevier Inc. All rights reserved.
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10 MeSH Terms
GABAA receptor biogenesis is impaired by the γ2 subunit febrile seizure-associated mutation, GABRG2(R177G).
Todd E, Gurba KN, Botzolakis EJ, Stanic AK, Macdonald RL
(2014) Neurobiol Dis 69: 215-24
MeSH Terms: Cell Membrane, Conserved Sequence, Cycloheximide, Endoplasmic Reticulum, Endoplasmic Reticulum-Associated Degradation, Glycosylation, HEK293 Cells, Humans, Models, Molecular, Mutation, Missense, Patch-Clamp Techniques, Protein Structure, Secondary, Protein Structure, Tertiary, Protein Synthesis Inhibitors, Protein Transport, Receptors, GABA-A, Seizures, Febrile, gamma-Aminobutyric Acid
Show Abstract · Added January 24, 2015
A missense mutation in the GABAA receptor γ2L subunit, R177G, was reported in a family with complex febrile seizures (FS). To gain insight into the mechanistic basis for these genetic seizures, we explored how the R177G mutation altered the properties of recombinant α1β2γ2L GABAA receptors expressed in HEK293T cells. Using a combination of electrophysiology, flow cytometry, and immunoblotting, we found that the R177G mutation decreased GABA-evoked whole-cell current amplitudes by decreasing cell surface expression of α1β2γ2L receptors. This loss of receptor surface expression resulted from endoplasmic reticulum (ER) retention of mutant γ2L(R177G) subunits, which unlike wild-type γ2L subunits, were degraded by ER-associated degradation (ERAD). Interestingly, when compared to the condition of homozygous γ2L(R177G) subunit expression, disproportionately low levels of γ2L(R177G) subunits reached the cell surface with heterozygous expression, indicating that wild-type γ2L subunits possessed a competitive advantage over mutant γ2L(R177G) subunits for receptor assembly and/or forward trafficking. Inhibiting protein synthesis with cycloheximide demonstrated that the R177G mutation primarily decreased the stability of an intracellular pool of unassembled γ2L subunits, suggesting that the mutant γ2L(R177G) subunits competed poorly with wild-type γ2L subunits due to impaired subunit folding and/or oligomerization. Molecular modeling confirmed that the R177G mutation could disrupt intrasubunit salt bridges, thereby destabilizing secondary and tertiary structure of γ2L(R177G) subunits. These findings support an emerging body of literature implicating defects in GABAA receptor biogenesis in the pathogenesis of genetic epilepsies (GEs) and FS.
Copyright © 2014. Published by Elsevier Inc.
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18 MeSH Terms
Histone deacetylase inhibitor enhances recovery after AKI.
Cianciolo Cosentino C, Skrypnyk NI, Brilli LL, Chiba T, Novitskaya T, Woods C, West J, Korotchenko VN, McDermott L, Day BW, Davidson AJ, Harris RC, de Caestecker MP, Hukriede NA
(2013) J Am Soc Nephrol 24: 943-53
MeSH Terms: Acute Kidney Injury, Animals, Disease Models, Animal, Fibrosis, Gentamicins, Histone Deacetylase 1, Histone Deacetylase Inhibitors, Ischemia, Kidney, Male, Mice, Mice, Inbred BALB C, Phenylbutyrates, Protein Synthesis Inhibitors, Recovery of Function, Zebrafish, Zebrafish Proteins
Show Abstract · Added February 10, 2014
At present, there are no effective therapies to ameliorate injury, accelerate recovery, or prevent postinjury fibrosis after AKI. Here, we sought to identify candidate compounds that accelerate recovery after AKI by screening for small molecules that increase proliferation of renal progenitor cells in zebrafish embryos. One compound identified from this screen was the histone deacetylase inhibitor methyl-4-(phenylthio)butanoate, which we subsequently administered to zebrafish larvae and mice 24-48 hours after inducing AKI. In zebrafish, treatment with the compound increased larval survival and proliferation of renal tubular epithelial cells. In mice, treatment accelerated recovery, reduced postinjury tubular atrophy and interstitial fibrosis, and increased the regenerative capacity of actively cycling renal tubular cells by decreasing the number of cells in G2/M arrest. These data suggest that accelerating recovery may be a viable approach to treating AKI and provide proof of concept that a screen in zebrafish embryos can identify therapeutic candidates for kidney injury.
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17 MeSH Terms
The sodium channel accessory subunit Navβ1 regulates neuronal excitability through modulation of repolarizing voltage-gated K⁺ channels.
Marionneau C, Carrasquillo Y, Norris AJ, Townsend RR, Isom LL, Link AJ, Nerbonne JM
(2012) J Neurosci 32: 5716-27
MeSH Terms: Analysis of Variance, Animals, Bacterial Proteins, Biophysics, Biotinylation, Cell Line, Transformed, Cerebral Cortex, Cycloheximide, Electric Stimulation, Endocytosis, Gene Expression Regulation, Green Fluorescent Proteins, Humans, Immunoprecipitation, Luminescent Proteins, Mass Spectrometry, Mice, Mice, Inbred C57BL, Mice, Knockout, Neurons, Patch-Clamp Techniques, Protein Synthesis Inhibitors, Proteomics, RNA, Small Interfering, Receptors, Transferrin, Shal Potassium Channels, Sodium Channels, Transfection, Voltage-Gated Sodium Channel beta-1 Subunit
Show Abstract · Added February 20, 2015
The channel pore-forming α subunit Kv4.2 is a major constituent of A-type (I(A)) potassium currents and a key regulator of neuronal membrane excitability. Multiple mechanisms regulate the properties, subcellular targeting, and cell-surface expression of Kv4.2-encoded channels. In the present study, shotgun proteomic analyses of immunoprecipitated mouse brain Kv4.2 channel complexes unexpectedly identified the voltage-gated Na⁺ channel accessory subunit Navβ1. Voltage-clamp and current-clamp recordings revealed that knockdown of Navβ1 decreases I(A) densities in isolated cortical neurons and that action potential waveforms are prolonged and repetitive firing is increased in Scn1b-null cortical pyramidal neurons lacking Navβ1. Biochemical and voltage-clamp experiments further demonstrated that Navβ1 interacts with and increases the stability of the heterologously expressed Kv4.2 protein, resulting in greater total and cell-surface Kv4.2 protein expression and in larger Kv4.2-encoded current densities. Together, the results presented here identify Navβ1 as a component of native neuronal Kv4.2-encoded I(A) channel complexes and a novel regulator of I(A) channel densities and neuronal excitability.
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29 MeSH Terms
KCNQ1/KCNE1 assembly, co-translation not required.
Vanoye CG, Welch RC, Tian C, Sanders CR, George AL
(2010) Channels (Austin) 4: 108-14
MeSH Terms: Animals, Brefeldin A, Cell Membrane, Cycloheximide, Endoplasmic Reticulum, Humans, Ion Channel Gating, KCNQ1 Potassium Channel, Kinetics, Membrane Potentials, Potassium, Potassium Channels, Voltage-Gated, Protein Synthesis Inhibitors, Protein Transport, Recombinant Proteins, Xenopus laevis
Show Abstract · Added November 21, 2018
Voltage-gated potassium channels are often assembled with accessory proteins that increase their functional diversity. KCNE proteins are small accessory proteins that modulate voltage-gated potassium (K(V)) channels. Although the functional effects of various KCNE proteins have been described, many questions remain regarding their assembly with the pore-forming subunits. For example, while previous experiments with some K(V) channels suggest that the association of the pore-subunit with the accessory subunits occurs co-translationally in the endoplasmic reticulum, it is not known whether KCNQ1 assembly with KCNE1 occurs in a similar manner to generate the medically important cardiac slow delayed rectifier current (I(Ks)). In this study we used a novel approach to demonstrate that purified recombinant human KCNE1 protein (prKCNE1) modulates KCNQ1 channels heterologously expressed in Xenopus oocytes resulting in generation of I(Ks). Incubation of KCNQ1-expressing oocytes with cycloheximide did not prevent I(Ks) expression following prKCNE1 injection. By contrast, incubation with brefeldin A prevented KCNQ1 modulation by prKCNE1. Moreover, injection of the trafficking-deficient KCNE1-L51H reduced KCNQ1 currents. Together, these observations indicate that while assembly of KCNE1 with KCNQ1 does not require co-translation, functional KCNQ1-prKCNE1 channels assemble early in the secretory pathway and reach the plasma membrane via vesicular trafficking.
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MeSH Terms
Treatment with protein synthesis inhibitors improves outcomes of secondary bacterial pneumonia after influenza.
Karlström A, Boyd KL, English BK, McCullers JA
(2009) J Infect Dis 199: 311-9
MeSH Terms: Ampicillin, Animals, Anti-Bacterial Agents, Bronchoalveolar Lavage Fluid, Clindamycin, Disease Models, Animal, Drug Screening Assays, Antitumor, Drug Therapy, Combination, Female, Inflammation, Influenza A virus, Lung, Mice, Mice, Inbred BALB C, N-Acetylmuramoyl-L-alanine Amidase, Orthomyxoviridae Infections, Pneumonia, Pneumococcal, Protein Synthesis Inhibitors, Tumor Necrosis Factor-alpha
Show Abstract · Added March 5, 2014
Pneumonia occurring as a secondary infection after influenza is a major cause of excess morbidity and mortality, despite the availability and use of antibiotics active against Streptococcus pneumoniae. We hypothesized that the use of a bacteriostatic protein synthesis inhibitor would improve outcomes by reducing the inflammatory response. BALB/cJ mice infected with influenza virus and superinfected with S. pneumoniae were treated with either the cell-wall-active antibiotic ampicillin or the protein synthesis inhibitor clindamycin or azithromycin. In the model, ampicillin therapy performed significantly worse (survival rate, 56%) than (1) clindamycin therapy used either alone (82%) or in combination with ampicillin (80%) and (2) azithromycin (92%). Improved survival appeared to be mediated by decreased inflammation manifested as lower levels of inflammatory cells and proinflammatory cytokines in the lungs and by observation of less-severe histopathologic findings. These data suggest that beta-lactam therapy may not be optimal as a first-line treatment for community-acquired pneumonia when it follows influenza.
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19 MeSH Terms
Multiple pathways involved in the biosynthesis of anandamide.
Liu J, Wang L, Harvey-White J, Huang BX, Kim HY, Luquet S, Palmiter RD, Krystal G, Rai R, Mahadevan A, Razdan RK, Kunos G
(2008) Neuropharmacology 54: 1-7
MeSH Terms: Animals, Arachidonic Acids, Cell Line, Transformed, Chromatography, High Pressure Liquid, Chromatography, Thin Layer, Drug Interactions, Endocannabinoids, Glycerophosphates, Hydrolases, Hydrolysis, Inositol Polyphosphate 5-Phosphatases, Lipopolysaccharides, Macrophages, Metabolic Networks and Pathways, Mice, Mice, Knockout, Neomycin, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Phospholipase D, Phosphoric Monoester Hydrolases, Polyunsaturated Alkamides, Protein Synthesis Inhibitors, Protein Tyrosine Phosphatase, Non-Receptor Type 22, RNA, Small Interfering, Transfection, Type C Phospholipases
Show Abstract · Added April 10, 2014
Endocannabinoids, including anandamide (arachidonoyl ethanolamide) have been implicated in the regulation of a growing number of physiological and pathological processes. Anandamide can be generated from its membrane phospholipid precursor N-arachidonoyl phosphatidylethanolamine (NAPE) through hydrolysis by a phospholipase D (NAPE-PLD). Recent evidence indicates, however, the existence of two additional, parallel pathways. One involves the sequential deacylation of NAPE by alpha,beta-hydrolase 4 (Abhd4) and the subsequent cleavage of glycerophosphate to yield anandamide, and the other one proceeds through phospholipase C-mediated hydrolysis of NAPE to yield phosphoanandamide, which is then dephosphorylated by phosphatases, including the tyrosine phosphatase PTPN22 and the inositol 5' phosphatase SHIP1. Conversion of synthetic NAPE to AEA by brain homogenates from wild-type and NAPE-PLD(-/-) mice can proceed through both the PLC/phosphatase and Abdh4 pathways, with the former being dominant at shorter (<10 min) and the latter at longer (60 min) incubations. In macrophages, the endotoxin-induced synthesis of anandamide proceeds uniquely through the phospholipase C/phosphatase pathway.
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26 MeSH Terms
Androgen receptor-mediated repression of novel target genes.
Prescott J, Jariwala U, Jia L, Cogan JP, Barski A, Pregizer S, Shen HC, Arasheben A, Neilson JJ, Frenkel B, Coetzee GA
(2007) Prostate 67: 1371-83
MeSH Terms: Androgen Antagonists, Anilides, Cell Line, Tumor, Cycloheximide, Dihydrotestosterone, Gene Expression Regulation, Neoplastic, Humans, Male, Nitriles, Prostatic Neoplasms, Protein Synthesis Inhibitors, RNA, Messenger, RNA, Small Interfering, Receptor, Muscarinic M1, Receptors, Androgen, Receptors, Muscarinic, Reverse Transcriptase Polymerase Chain Reaction, Tosyl Compounds, Transfection
Show Abstract · Added September 23, 2013
BACKGROUND - The androgen receptor (AR) plays a pivotal role in prostate cancer (PCa) initiation and progression. To date, studies have focused disproportionately on androgen-stimulated genes such as prostate-specific antigen (PSA), while repressed genes have gained little attention, even though they too may be involved in regulating cell growth, differentiation, and apoptosis.
METHODS - ChIP Display was used to identify putative AR target genes in the ablation-resistant human PCa cell line, C4-2B. Quantitative real-time reverse transcription-PCR analysis was used to measure gene expression in cells subjected to dihydrotestosterone (DHT) timecourse and dose-response, as well as AR knock-down and bicalutamide-treatments.
RESULTS - We report on three genes, KIAA1217, CHRM1, and WBSCR28, which were newly identified in a screen for AR-occupied regions in C4-2B PCa cells, and which were repressed by treatment with DHT. AR knock-down resulted in increased KIAA1217, CHRM1, and WBSCR28 mRNA, indicating that, like PSA stimulation, AR represses these three genes even in the absence of added ligand. DHT decreased KIAA1217 and CHRM1 pre-mRNA levels, suggesting AR-mediated transcriptional inhibition. Cycloheximide attenuated DHT-mediated repression of CHRM1, suggesting the requirement of new protein synthesis. Furthermore, bicalutamide treatment did not mimic, but rather antagonized DHT-mediated KIAA1217 repression. Unlike the handful of androgen-repressed genes studied thus far, AR occupancy at KIAA1217, CHRM1, and WBSCR28 was mapped outside their respective 5'-promoter regions.
CONCLUSIONS - Many more genes likely share AR-mediated gene repression through distal regulatory elements. Further study of such targets and their transcriptional regulation may help explain the receptor's tumorigenicity in PCa.
2007 Wiley-Liss, Inc
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19 MeSH Terms