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https://www.readbyqxmd.com/read/29311306/mechanism-specific-assay-design-facilitates-the-discovery-of-nav1-7-selective-inhibitors
#1
Tania Chernov-Rogan, Tianbo Li, Gang Lu, Henry Verschoof, Kuldip Khakh, Steven W Jones, Maureen H Beresini, Chang Liu, Daniel F Ortwine, Steven J McKerrall, David H Hackos, Daniel Sutherlin, Charles J Cohen, Jun Chen
Many ion channels, including Nav1.7, Cav1.3, and Kv1.3, are linked to human pathologies and are important therapeutic targets. To develop efficacious and safe drugs, subtype-selective modulation is essential, but has been extremely difficult to achieve. We postulate that this challenge is caused by the poor assay design, and investigate the Nav1.7 membrane potential assay, one of the most extensively employed screening assays in modern drug discovery. The assay uses veratridine to activate channels, and compounds are identified based on the inhibition of veratridine-evoked activities...
January 8, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29283926/interactions-of-propofol-with-human-voltage-gated-kv1-5-channel-determined-by-docking-simulation-and-mutagenesis-analyses
#2
Akiko Kojima, Yutaka Fukushima, Yuki Ito, Wei-Guang Ding, Rika Ueda, Tomoyoshi Seto, Hirotoshi Kitagawa, Hiroshi Matsuura
Propofol blocks the voltage-gated human Kv1.5 (hKv1.5) channel by preferentially affecting in its open state. A previous mutational study suggested that several amino acids within the pore region of the hKv1.5 channel are involved in mediating the blocking action of propofol. The present investigation was undertaken to elucidate the predicted binding modes of propofol within the pore cavity of the open-state hKv1.5 channel, using computational docking and mutagenesis approaches. The docking simulation using a homology model of the hKv1...
January 2018: Journal of Cardiovascular Pharmacology
https://www.readbyqxmd.com/read/29209776/hyperoxia-induced-cardiotoxicity-and-ventricular-remodeling-in-type-ii-diabetes-mice
#3
Jennifer Leigh Rodgers, Eva Samal, Subhra Mohapatra, Siva Kumar Panguluri
Hyperoxia, or supplemental oxygen, is regularly used in the clinical setting for critically ill patients in ICU. However, several recent studies have demonstrated the negative impact of this treatment in patients in critical care, including increased rates of lung and cardiac injury, as well as increased mortality. The purpose of this study was to determine the predisposition for arrhythmias and electrical remodeling in a type 2 diabetic mouse model (db/db), as a result of hyperoxia treatment. For this, db/db and their heterozygous controls were treated with hyperoxia (> 90% oxygen) or normoxia (normal air) for 72-h...
December 5, 2017: Heart and Vessels
https://www.readbyqxmd.com/read/29172176/atp-sensitive-and-maxi-potassium-channels-regulate-brl-37344-induced-tocolysis-in-buffaloes-an-in%C3%A2-vitro-study
#4
Vipin Sharma, Sooraj V Nair, Pooja Jaitley, Udayraj P Nakade, Abhishek Sharma, Soumen Choudhury, Satish Kumar Garg
Cellular coupling of beta3-adrenoceptors (β3-ADR) to potassium channels in myometrium is largely unknown. In vitro study was undertaken to unravel the presence of β3-adrenergic receptors (ADR) and the role of K(+)-channels in mediating β3-ADR-induced relaxation in isolated myometrial strips from cyclic non-pregnant water buffaloes. Isometric tension was recorded in isolated myometrial strips using data acquisition system based physiograph. Compared to SR 59230A, BRL 37344 was found to be more potent in inducing β3-dependent myometrial relaxation which was significantly (p < 0...
November 13, 2017: Theriogenology
https://www.readbyqxmd.com/read/29168928/regulation-of-kv1-4-potassium-channels-by-pkc-and-ampk-kinases
#5
Martin Nybo Andersen, Lasse Skibsbye, Arnela Saljic, Martin Zahle Larsen, Hanne Borger Rasmussen, Thomas Jespersen
Over the last years extensive kinase-mediated regulation of a number of voltage-gated potassium (Kv) channels important in cardiac electrophysiology has been reported. This includes regulation of Kv1.5, Kv7.1 and Kv11.1 cell surface expression, where the kinase-mediated regulation appears to center around the ubiquitin ligase Nedd4-2. In the present study we examined whether Kv1.4, constituting the cardiac Ito,s current, is subject to similar regulation. In the epithelial Madin-Darby Canine Kidney (MDCK) cell line, which constitutes a highly reproducible model system for addressing membrane targeting, we find, by confocal microscopy, that Kv1...
November 23, 2017: Channels
https://www.readbyqxmd.com/read/29139614/human-dental-stem-cell-derived-transgene-free-ipscs-generate-functional-neurons-via-embryoid-body-mediated-and-direct-induction-methods
#6
Ikbale El Ayachi, Jun Zhang, Xiao-Ying Zou, Zongdong Yu, Wei Wei, Kristen M S O'Connell, George T-J Huang
Induced pluripotent stem cells (iPSCs) give rise to neural stem/progenitor cells (NSCs), serving as a good source for neural regeneration. Here, we established transgene-free (TF) iPSCs from dental stem cells (DSCs) and determined their capacity to differentiate into functional neurons in vitro. Generated TF iPSCs from stem cells of apical papilla (SCAP) and dental pulp stem cells (DPSCs) underwent two methods -- embryoid body (EB)-mediated and direct induction, to guide TF-DSC iPSCs along with H9 or H9 Syn-GFP (human embryonic stem cells) into functional neurons in vitro...
November 15, 2017: Journal of Tissue Engineering and Regenerative Medicine
https://www.readbyqxmd.com/read/28933692/a-quantitative-hypermorphic-cngc-allele-confers-ectopic-calcium-flux-and-impairs-cellular-development
#7
David M Chiasson, Kristina Haage, Katharina Sollweck, Andreas Brachmann, Petra Dietrich, Martin Parniske
The coordinated control of Ca(2+) signaling is essential for development in eukaryotes. Cyclic nucleotide-gated channel (CNGC) family members mediate Ca(2+) influx from cellular stores in plants(1-4). Here we report the unusual genetic behavior of a quantitative gain-of-function CNGC mutation (brush) in Lotus japonicus resulting in a leaky tetrameric channel. brush resides in a cluster of redundant CNGCs encoding subunits which resemble metazoan voltage-gated potassium (Kv1-Kv4) channels in assembly and gating properties...
September 21, 2017: ELife
https://www.readbyqxmd.com/read/28877968/action-potential-broadening-in-capsaicin-sensitive-drg-neurons-from-frequency-dependent-reduction-of-kv3-current
#8
Pin W Liu, Nathaniel T Blair, Bruce P Bean
Action potential (AP) shape is a key determinant of cellular electrophysiological behavior. We found that in small-diameter, capsaicin-sensitive dorsal root ganglia neurons corresponding to nociceptors (from rats of either sex), stimulation at frequencies as low as 1 Hz produced progressive broadening of the APs. Stimulation at 10 Hz for 3 s resulted in an increase in AP width by an average of 76 ± 7% at 22°C and by 38 ± 3% at 35°C. AP clamp experiments showed that spike broadening results from frequency-dependent reduction of potassium current during spike repolarization...
October 4, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28869943/targeting-the-potassium-channel-kv1-3-kills-glioblastoma-cells
#9
Elisa Venturini, Luigi Leanza, Michele Azzolini, Stephanie Kadow, Andrea Mattarei, Michael Weller, Ghazaleh Tabatabai, Michael J Edwards, Mario Zoratti, Cristina Paradisi, Ildikò Szabò, Erich Gulbins, Katrin Anne Becker
BACKGROUND/AIMS: Glioblastoma (GBM) is one of the most aggressive cancers, counting for a high number of the newly diagnosed patients with central nervous system (CNS) cancers in the United States and Europe. Major features of GBM include aggressive and invasive growth as well as a high resistance to treatment. Kv1.3, a potassium channel of the shaker family, is expressed in the inner mitochondrial membrane of many cancer cells. Inhibition of mitochondrial Kv1.3 was shown to induce apoptosis in several tumor cells at doses that were not lethal for normal cells...
September 1, 2017: Neuro-Signals
https://www.readbyqxmd.com/read/28867730/up-regulation-of-the-voltage-gated-kv2-1-k-channel-in-the-renal-arterial-myocytes-of-dahl-salt-sensitive-hypertensive-rats
#10
Kazunobu Ogiwara, Susumu Ohya, Yoshiaki Suzuki, Hisao Yamamura, Yuji Imaizumi
Salt-sensitive hypertension induces renal injury via decreased blood flow in the renal artery (RA), and ion channel dysfunction in RA myocytes (RAMs) may be involved in the higher renal vascular resistance. We examined the effects of several voltage-gated K(+) (KV) channel blockers on the resting tension in endothelium-denuded RA strips and delayed-rectifier K(+) currents in RAMs of Dahl salt-sensitive hypertensive rats (Dahl-S) fed with low- (Dahl-LS) and high-salt diets (Dahl-HS). The tetraethylammonium (TEA)-induced contraction in RA strips were significantly larger in Dahl-HS than Dahl-LS...
2017: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28830445/responses-of-rat-and-mouse-primary-microglia-to-pro-and-anti-inflammatory-stimuli-molecular-profiles-k-channels-and-migration
#11
Doris Lam, Starlee Lively, Lyanne C Schlichter
BACKGROUND: Acute CNS damage is commonly studied using rat and mouse models, but increasingly, molecular analysis is finding species differences that might affect the ability to translate findings to humans. Microglia can undergo complex molecular and functional changes, often studied by in vitro responses to discrete activating stimuli. There is considerable evidence that pro-inflammatory (M1) activation can exacerbate tissue damage, while anti-inflammatory (M2) states help resolve inflammation and promote tissue repair...
August 22, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/28802123/clathrodin-hymenidin-and-oroidin-and-their-synthetic-analogues-as-inhibitors-of-the-voltage-gated-potassium-channels
#12
Nace Zidar, Aleš Žula, Tihomir Tomašič, Marc Rogers, Robert W Kirby, Jan Tytgat, Steve Peigneur, Danijel Kikelj, Janez Ilaš, Lucija Peterlin Mašič
We have prepared three alkaloids from the Agelas sponges, clathrodin, hymenidin and oroidin, and a series of their synthetic analogues, and evaluated their inhibitory effect against six isoforms of the Kv1 subfamily of voltage-gated potassium channels, Kv1.1-Kv1.6, expressed in Chinese Hamster ovary (CHO) cells using automated patch clamp electrophysiology assay. The most potent inhibitor was the (E)-N-(3-(2-amino-1H-imidazol-4-yl)allyl)-4,5-dichloro-1H-pyrrole-2-carboxamide (6g) with IC50 values between 1...
October 20, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28793216/smit1-modifies-kcnq-channel-function-and-pharmacology-by-physical-interaction-with-the-pore
#13
Rían W Manville, Daniel L Neverisky, Geoffrey W Abbott
Voltage-gated potassium channels of the KCNQ (Kv7) subfamily are essential for control of cellular excitability and repolarization in a wide range of cell types. Recently, we and others found that some KCNQ channels functionally and physically interact with sodium-dependent solute transporters, including myo-inositol transporters SMIT1 and SMIT2, potentially facilitating various modes of channel-transporter signal integration. In contrast to indirect effects such as channel regulation by SMIT-transported, myo-inositol-derived phosphatidylinositol 4,5-bisphosphate (PIP2), the mechanisms and functional consequences of the physical interaction of channels with transporters have been little studied...
August 8, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28738160/atrial-selective-k-channel-blockers-potential-antiarrhythmic-drugs-in-atrial-fibrillation
#14
Ursula Ravens
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...
November 2017: Canadian Journal of Physiology and Pharmacology
https://www.readbyqxmd.com/read/28729840/cardiac-subtype-specific-modeling-of-kv1-5-ion-channel-deficiency-using-human-pluripotent-stem-cells
#15
Maike Marczenke, Ilaria Piccini, Isabella Mengarelli, Jakob Fell, Albrecht Röpke, Guiscard Seebohm, Arie O Verkerk, Boris Greber
The ultrarapid delayed rectifier K(+) current (IKur), mediated by Kv1.5 channels, constitutes a key component of the atrial action potential. Functional mutations in the underlying KCNA5 gene have been shown to cause hereditary forms of atrial fibrillation (AF). Here, we combine targeted genetic engineering with cardiac subtype-specific differentiation of human induced pluripotent stem cells (hiPSCs) to explore the role of Kv1.5 in atrial hiPSC-cardiomyocytes. CRISPR/Cas9-mediated mutagenesis of integration-free hiPSCs was employed to generate a functional KCNA5 knockout...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28723914/safety-and-pharmacodynamics-of-dalazatide-a-kv1-3-channel-inhibitor-in-the-treatment-of-plaque-psoriasis-a-randomized-phase-1b-trial
#16
RANDOMIZED CONTROLLED TRIAL
Eric J Tarcha, Chelsea M Olsen, Peter Probst, David Peckham, Ernesto J Muñoz-Elías, James G Kruger, Shawn P Iadonato
BACKGROUND: Dalazatide is a specific inhibitor of the Kv1.3 potassium channel. The expression and function of Kv1.3 channels are required for the function of chronically activated memory T cells, which have been shown to be key mediators of autoimmune diseases, including psoriasis. OBJECTIVE: The primary objective was to evaluate the safety of repeat doses of dalazatide in adult patients with mild-to-moderate plaque psoriasis. Secondary objectives were to evaluate clinical proof of concept and the effects of dalazatide on mediators of inflammation in the blood and on chronically activated memory T cell populations...
2017: PloS One
https://www.readbyqxmd.com/read/28710444/ergodicity-breaking-on-the-neuronal-surface-emerges-from-random-switching-between-diffusive-states
#17
Aleksander Weron, Krzysztof Burnecki, Elizabeth J Akin, Laura Solé, Michał Balcerek, Michael M Tamkun, Diego Krapf
Stochastic motion on the surface of living cells is critical to promote molecular encounters that are necessary for multiple cellular processes. Often the complexity of the cell membranes leads to anomalous diffusion, which under certain conditions it is accompanied by non-ergodic dynamics. Here, we unravel two manifestations of ergodicity breaking in the dynamics of membrane proteins in the somatic surface of hippocampal neurons. Three different tagged molecules are studied on the surface of the soma: the voltage-gated potassium and sodium channels Kv1...
July 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28655649/interregional-electro-mechanical-heterogeneity-in-the-rabbit-myocardium
#18
REVIEW
Franz F Dressler, Ilona Bodi, Marius Menza, Robin Moss, Heiko Bugger, Christoph Bode, Jan C Behrends, Gunnar Seemann, Katja E Odening
BACKGROUND: Increased electrical heterogeneity has been causatively linked to arrhythmic disorders, yet the knowledge about physiological heterogeneity remains incomplete. This study investigates regional electro-mechanical heterogeneities in rabbits, one of the key animal models for arrhythmic disorders. METHODS AND FINDINGS: 7 wild-type rabbits were examined by phase-contrast magnetic resonance imaging in vivo to assess cardiac wall movement velocities. Using a novel data-processing algorithm regional contraction-like profiles were calculated...
June 24, 2017: Progress in Biophysics and Molecular Biology
https://www.readbyqxmd.com/read/28552341/methamphetamine-potentiates-hiv-1gp120-induced-microglial-neurotoxic-activity-by-enhancing-microglial-outward-k-current
#19
Jianuo Liu, Enquan Xu, Guihua Tu, Han Liu, Jiangtao Luo, Huangui Xiong
Methamphetamine (Meth) abuse not only increases the risk of human immunodeficiency virus-1 (HIV-1) infection, but exacerbates HIV-1-associated neurocognitive disorders (HAND) as well. The mechanisms underlying the co-morbid effect are not fully understood. Meth and HIV-1 each alone interacts with microglia and microglia express voltage-gated potassium (KV) channel KV1.3. To understand whether KV1.3 functions an intersecting point for Meth and HIV-1, we studied the augment effect of Meth on HIV-1 glycoprotein 120 (gp120)-induced neurotoxic activity in cultured rat microglial cells...
July 2017: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/28549558/the-kv1-3-channel-blocker-vm24-enhances-muscle-glucose-transporter-4-mobilization-but-does-not-reduce-body-weight-gain-in-diet-induced-obese-male-rats
#20
Lorraine Jaimes-Hoy, Georgina B Gurrola, Miguel Cisneros, Patricia Joseph-Bravo, Lourival D Possani, Jean-Louis Charli
AIMS: Voltage-gated potassium channels 1.3 (Kv1.3) can be targeted to reduce diet-induced obesity and insulin resistance in mice. Since species-specific differences in Kv1.3 expression and pharmacology have been observed, we tested the effect of Vm24, a high-affinity specific blocker of Kv1.3 channels from Vaejovis mexicanus smithi, on body weight (BW), glucose tolerance and insulin resistance in diet-induced obese rats. MATERIALS AND METHODS: Young adult male Wistar rats were switched to a high-fat/high-fructose (HFF) diet...
July 15, 2017: Life Sciences
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