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https://www.readbyqxmd.com/read/29156097/4-aminopyridine-a-pan-kv-channel-inhibitor-that-enhances-kv7-4-currents-and-inhibits-noradrenaline-mediated-contraction-of-rat-mesenteric-small-arteries
#1
Makhala M Khammy, Sukhan Kim, Bo H Bentzen, Soojung Lee, Inyeoung Choi, Christian Aalkjaer, Thomas A Jepps
BACKGROUND AND PURPOSE: Kv7.4 and Kv7.5 channels are regulators of vascular tone. 4-aminopyridine (4-AP) is considered a broad inhibitor of voltage-gated potassium (KV ) channels, with little inhibitory effect on Kv7 family members at millimolar concentrations. However, the effect of 4-AP on Kv7 channels has not been systematically studied. The aim of this study was to investigate the pharmacological activity of 4-AP on Kv7.4 and Kv7.5 channels and characterise the effect of 4-AP on rat resistance arteries...
November 20, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29155148/functional-properties-and-mechanism-of-action-of-pptq-an-allosteric-agonist-and-low-nanomolar-positive-allosteric-modulator-at-gabaa-receptors
#2
Nawid Madjroh, Emma Rie Olander, Christoffer Bundgaard, Pella Cecilia Söderhielm, Anders A Jensen
The former sedative-hypnotic and recreational drug methaqualone (Quaalude) is a moderately potent, non-selective positive allosteric modulator (PAM) at GABAA receptors (GABAARs) (Hammer et al., 2015). In the present study, we have identified a novel methaqualone analog, 2-phenyl-3-(p-tolyl)quinazolin-4(3H)-one (PPTQ), in a screening of 67 analogs at five αβ2γ2S GABAAR subtypes and delineated its functional properties and mechanism of action at wild-type and mutant GABAARs expressed in Xenopus oocytes by two-electrode voltage clamp electrophysiology...
November 15, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29150461/gabaa-receptor-activation-in-the-allosteric-coagonist-model-framework-relationship-between-ec50-and-basal-activity
#3
Gustav Akk, Daniel J Shin, Allison L Germann, Joseph H Steinbach
The concerted transition model for multimeric proteins is a simple formulation for analyzing the behavior of transmitter-gated ion channels. Here, we use the model to examine the relationship between the EC50 for activation of the GABAA receptor by the transmitter GABA and basal activity employing concatemeric ternary GABAA receptors expressed in Xenopus oocytes. The basal activity reflects receptor function in the absence of transmitter, and can be changed either by mutation to increase constitutive activity, or by addition of a second agonist (acting at a different site) to increase background activity...
November 17, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/29142255/a-nonredundant-role-for-the-trpm6-channel-in-neural-tube-closure
#4
Yuko Komiya, Zhiyong Bai, Na Cai, Liping Lou, Namariq Al-Saadi, Courtney Mezzacappa, Raymond Habas, Loren W Runnels
In humans, germline mutations in Trpm6 cause autosomal dominant hypomagnesemia with secondary hypocalcemia disorder. Loss of Trpm6 in mice also perturbs cellular magnesium homeostasis but additionally results in early embryonic lethality and neural tube closure defects. To define the mechanisms by which TRPM6 influences neural tube closure, we functionally characterized the role of TRPM6 during early embryogenesis in Xenopus laevis. The expression of Xenopus TRPM6 (XTRPM6) is elevated at the onset of gastrulation and is concentrated in the lateral mesoderm and ectoderm at the neurula stage...
November 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29142207/phosphorylation-dynamics-dominate-the-regulated-proteome-during-early-xenopus-development
#5
Elizabeth H Peuchen, Olivia F Cox, Liangliang Sun, Alex S Hebert, Joshua J Coon, Matthew M Champion, Norman J Dovichi, Paul W Huber
The earliest stages of animal development are largely controlled by changes in protein phosphorylation mediated by signaling pathways and cyclin-dependent kinases. In order to decipher these complex networks and to discover new aspects of regulation by this post-translational modification, we undertook an analysis of the X. laevis phosphoproteome at seven developmental stages beginning with stage VI oocytes and ending with two-cell embryos. Concurrent measurement of the proteome and phosphoproteome enabled measurement of phosphosite occupancy as a function of developmental stage...
November 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29142093/developmental-changes-in-spinal-neuronal-properties-motor-network-configuration-and-neuromodulation-at-free-swimming-stages-of-xenopus-frog-tadpoles
#6
Stephen Paul Currie, Keith Thomas Sillar
We describe a novel preparation of the isolated brainstem and spinal cord from pro-metamorphic tadpole stages of the South African clawed frog (Xenopus laevis) that permits whole cell patch-clamp recordings from neurons in the ventral spinal cord. Previous research on earlier stages of the same species has provided one of the most detailed understandings of the design and operation of a CPG circuit. Here we have addressed how development sculpts complexity from this more basic circuit. The preparation generates bouts of fictive swimming activity either spontaneously or in response to electrical stimulation of the optic tectum, allowing an investigation into how the neuronal properties, activity patterns and neuromodulation of locomotor rhythm generation change during development...
November 15, 2017: Journal of Neurophysiology
https://www.readbyqxmd.com/read/29141955/the-constant-threat-from-a-non-native-predator-increases-tail-muscle-and-fast-start-swimming-performance-in-xenopus-tadpoles
#7
Tsukasa Mori, Yukio Yanagisawa, Yoichiro Kitani, Goshi Yamamoto, Naoko Goto-Inoue, Tadashi Kimura, Keiko Kashiwagi, Akihiko Kashiwagi
Predator-induced phenotypic plasticity is the ability of prey to adapt to their native predator. However, owing to environmental changes, encounters with unknown predators are inevitable. Therefore, study of prey and non-native predator interaction will reveal the primary stages of adaptive strategies in prey-predator interactions in the context of evolutionary processes. Here, Xenopus tadpoles exposed to a non-native predator, a larval salamander, showed a significant increase in body weight and tail length to body length ratio...
November 15, 2017: Biology Open
https://www.readbyqxmd.com/read/29141881/it-s-not-all-black-and-white-visual-scene-parameters-influence-optokinetic-reflex-performance-in-xenopus-laevis-tadpoles
#8
Céline M Gravot, Alexander G Knorr, Stefan Glasauer, Hans Straka
The maintenance of visual acuity during active and passive body motion is ensured by gaze-stabilizing reflexes that aim at minimizing retinal image slip. For the optokinetic reflex (OKR), large-field visual motion of the surround forms the essential stimulus that activates eye movements. Properties of the moving visual world influence cognitive motion perception and the estimation of visual image velocity. Therefore, the performance of brainstem-mediated visuo-motor behaviors might also depend on image scene characteristics...
November 15, 2017: Journal of Experimental Biology
https://www.readbyqxmd.com/read/29141876/xenopus-and-the-art-of-oxygen-maintenance
#9
Glenn J Tattersall, Warren W Burggren
No abstract text is available yet for this article.
November 15, 2017: Journal of Experimental Biology
https://www.readbyqxmd.com/read/29140249/maternal-gdf3-is-an-obligatory-cofactor-in-nodal-signaling-for-embryonic-axis-formation-in-zebrafish
#10
Brent W Bisgrove, Yi-Chu Su, H Joseph Yost
Zebrafish Gdf3 (Dvr1) is a member of the TGFb superfamily of cell signaling ligands that includes Xenopus Vg1 and mammalian Gdf1/3. Surprisingly, engineered homozygous mutants in zebrafish have no apparent phenotype. Elimination of Gdf3 in oocytes of maternal-zygotic mutants results in embryonic lethality that can be fully rescued with gdf3 RNA, demonstrating that Gdf3 is required only early in development, beyond which mutants are viable and fertile. Gdf3 mutants are refractory to Nodal ligands and Nodal repressor Lefty1...
November 15, 2017: ELife
https://www.readbyqxmd.com/read/29138502/crystal-structures-of-the-mitochondrial-deacylase-sirtuin-4-reveal-isoform-specific-acyl-recognition-and-regulation-features
#11
Martin Pannek, Zeljko Simic, Matthew Fuszard, Marat Meleshin, Dante Rotili, Antonello Mai, Mike Schutkowski, Clemens Steegborn
Sirtuins are evolutionary conserved NAD(+)-dependent protein lysine deacylases. The seven human isoforms, Sirt1-7, regulate metabolism and stress responses and are considered therapeutic targets for aging-related diseases. Sirt4 locates to mitochondria and regulates fatty acid metabolism and apoptosis. In contrast to the mitochondrial deacetylase Sirt3 and desuccinylase Sirt5, no prominent deacylase activity and structural information are available for Sirt4. Here we describe acyl substrates and crystal structures for Sirt4...
November 15, 2017: Nature Communications
https://www.readbyqxmd.com/read/29134638/inhibition-of-acid-sensing-ion-channels-by-diminazene-and-apetx2-evoke-partial-and-highly-variable-antihyperalgesia-in-a-rat-model-of-inflammatory-pain
#12
Jia Yu Peppermint Lee, Natalie J Saez, Ben Cristofori-Armstrong, Raveendra Anangi, Glenn F King, Maree T Smith, Lachlan D Rash
BACKGROUND AND PURPOSE: Acid-sensing ion channels (ASICs) are primary acid sensors in mammals, with the ASIC1b and ASIC3 subtypes being involved in peripheral nociception. The antiprotozoal drug diminazene is a moderately potent ASIC inhibitor but its analgesic activity has not been assessed. EXPERIMENTAL APPROACH: We determined the ASIC subtype selectivity of diminazene and the mechanism by which it inhibits ASICs using voltage-clamp electrophysiology of Xenopus oocytes expressing ASICs 1-3...
November 14, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29134157/overland-movement-in-african-clawed-frogs-xenopus-laevis-empirical-dispersal-data-from-within-their-native-range
#13
F André De Villiers, John Measey
Dispersal forms are an important component of the ecology of many animals, and reach particular importance for predicting ranges of invasive species. African clawed frogs (Xenopus laevis) move overland between water bodies, but all empirical studies are from invasive populations with none from their native southern Africa. Here we report on incidents of overland movement found through a capture-recapture study carried out over a three year period in Overstrand, South Africa. The maximum distance moved was 2...
2017: PeerJ
https://www.readbyqxmd.com/read/29133411/specific-inhibition-of-gpcr-independent-g-protein-signaling-by-a-rationally-engineered-protein
#14
Anthony Leyme, Arthur Marivin, Marcin Maziarz, Vincent DiGiacomo, Maria P Papakonstantinou, Prachi P Patel, Juan B Blanco-Canosa, Isha A Walawalkar, Gonzalo Rodriguez-Davila, Isabel Dominguez, Mikel Garcia-Marcos
Activation of heterotrimeric G proteins by cytoplasmic nonreceptor proteins is an alternative to the classical mechanism via G protein-coupled receptors (GPCRs). A subset of nonreceptor G protein activators is characterized by a conserved sequence named the Gα-binding and activating (GBA) motif, which confers guanine nucleotide exchange factor (GEF) activity in vitro and promotes G protein-dependent signaling in cells. GBA proteins have important roles in physiology and disease but remain greatly understudied...
November 13, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29127702/towards-functional-selectivity-for-%C3%AE-6%C3%A2-3%C3%AE-2-gabaa-receptors-a-series-of-novel-pyrazoloquinolinones
#15
Marco Treven, David C B Siebert, Raphael Holzinger, Konstantina Bampali, Jure Fabjan, Zdravko Varagic, Laurin Wimmer, Friederike Steudle, Petra Scholze, Michael Schnürch, Marko D Mihovilovic, Margot Ernst
BACKGROUND AND PURPOSE: The γ - aminobutyric acid type A (GABAA ) receptors are ligand-gated ion channels which play an important role in neurotransmission. Their variety of binding sites serves as an appealing target for many clinically relevant drugs. Here, we explored the functional selectivity of modulatory effects at specific extracellular α+/®- interfaces, using a systematically varied series of pyrazoloquinolinones. EXPERIMENTAL APPROACH: Recombinant GABAA receptors were expressed in Xenopus laevis oocytes and modulatory effects on GABA elicited currents by the newly synthesized and the reference compounds were investigated by the two-electrode voltage clamp method...
November 11, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29127278/the-north-american-bullfrog-draft-genome-provides-insight-into-hormonal-regulation-of-long-noncoding-rna
#16
S Austin Hammond, René L Warren, Benjamin P Vandervalk, Erdi Kucuk, Hamza Khan, Ewan A Gibb, Pawan Pandoh, Heather Kirk, Yongjun Zhao, Martin Jones, Andrew J Mungall, Robin Coope, Stephen Pleasance, Richard A Moore, Robert A Holt, Jessica M Round, Sara Ohora, Branden V Walle, Nik Veldhoen, Caren C Helbing, Inanc Birol
Frogs play important ecological roles, and several species are important model organisms for scientific research. The globally distributed Ranidae (true frogs) are the largest frog family, and have substantial evolutionary distance from the model laboratory Xenopus frog species. Unfortunately, there are currently no genomic resources for the former, important group of amphibians. More widely applicable amphibian genomic data is urgently needed as more than two-thirds of known species are currently threatened or are undergoing population declines...
November 10, 2017: Nature Communications
https://www.readbyqxmd.com/read/29127015/oxotremorine-m-potentiates-nmda-receptors-by-muscarinic-receptor-dependent-and-independent-mechanisms
#17
Ruud Zwart, Hannah Reed, Emanuele Sher
Muscarinic acetylcholine M1 receptors play an important role in synaptic plasticity in the hippocampus and cortex. Potentiation of NMDA receptors as a consequence of muscarinic acetylcholine M1 receptor activation is a crucial event mediating the cholinergic modulation of synaptic plasticity, which is a cellular mechanism for learning and memory. In Alzheimer's disease, the cholinergic input to the hippocampus and cortex is severely degenerated, and agonists or positive allosteric modulators of M1 receptors are therefore thought to be of potential use to treat the deficits in cognitive functions in Alzheimer's disease...
November 7, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29126198/thyroid-hormone-receptor-%C3%AE-and-%C3%AE-knockout-xenopus-tropicalis-tadpoles-reveal-subtype-specific-roles-during-development
#18
Keisuke Nakajima, Ichiro Tazawa, Yoshio Yaoita
Thyroid hormone (TH) binds TH receptor alpha (TRα) and beta (TRβ) receptors to induce amphibian metamorphosis. Whereas TH signalling has been well studied, functional differences between TRα and TRβ during this process have not been characterized. To understand how each TR contributes to metamorphosis, we generated TRα- and TRβ-knockout tadpoles of Xenopus tropicalis and examined developmental abnormalities, histology of the tail and intestine, and mRNA expression of genes encoding extracellular matrix (ECM)-degrading enzymes...
November 3, 2017: Endocrinology
https://www.readbyqxmd.com/read/29119247/wall-following-in-xenopus-laevis-is-barrier-driven
#19
Sara Hänzi, Hans Straka
The tendency of animals to follow boundaries within their environment can serve as a strategy for spatial learning or defensive behaviour. We examined whether Xenopus laevis tadpoles and froglets employ such a strategy by characterizing their swimming pattern in a square tank with shallow water. Trajectories obtained from video recordings were analysed for proximity to the nearest wall. With the exception of young larvae, the vast majority of animals (both tadpoles and froglets) spent a disproportionately large amount of time near the wall...
November 8, 2017: Journal of Comparative Physiology. A, Neuroethology, Sensory, Neural, and Behavioral Physiology
https://www.readbyqxmd.com/read/29118359/visualization-and-quantification-of-injury-to-the-ciliated-epithelium-using-quantitative-flow-imaging-and-speckle-variance-optical-coherence-tomography
#20
Ute A Gamm, Brendan K Huang, Emily K Mis, Mustafa K Khokha, Michael A Choma
Mucociliary flow is an important defense mechanism in the lung to remove inhaled pathogens and pollutants. Disruption of ciliary flow can lead to respiratory infections. Multiple factors, from drugs to disease can cause an alteration in ciliary flow. However, less attention has been given to injury of the ciliated epithelium. In this study, we show how optical coherence tomography (OCT) can be used to investigate injury to the ciliated epithelium in a multi-contrast setting. We used particle tracking velocimetry (PTV-OCT) to investigate the cilia-driven flow field and 3D speckle variance imaging to investigate size and extent of injury caused to the skin of Xenopus embryos...
November 8, 2017: Scientific Reports
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