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https://www.readbyqxmd.com/read/29789377/polyamine-modulation-of-anticonvulsant-drug-response-a-potential-mechanism-contributing-to-pharmacoresistance-in-chronic-epilepsy
#1
Niklas Michael Beckonert, Thoralf Opitz, Julika Pitsch, Patrício Soares da Silva, Heinz Beck
Despite the development of numerous novel anticonvulsant drugs, approximately 30% of epilepsy patients remain refractory to antiepileptic drugs (AEDs). Many established and novel AEDs reduce hyperexcitability via voltage- and use-dependent inhibition of voltage-gated Na+ channels. For the widely-used anticonvulsant carbamazepine (CBZ), use-dependent block of Na+ channels is significantly reduced both in experimental and human epilepsy. However, the molecular underpinnings of this potential cellular mechanism for pharmacoresistance have remained enigmatic...
May 22, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29788971/differential-regulation-of-nimodipine-sensitive-and-insensitive-ca-2-influx-by-the-na-ca-2-exchanger-and-mitochondria-in-the-rat-suprachiasmatic-nucleus-neurons
#2
Pi-Cheng Cheng, Yi-Chi Wang, Ya-Shuan Chen, Ruo-Ciao Cheng, Jyh-Jeen Yang, Rong-Chi Huang
BACKGROUND: Transmembrane Ca2+ influx is critical for molecular rhythmicity, metabolic activity, and neuropeptide release in the central clock of the suprachiasmatic nucleus (SCN). We previously reported that both the Na+ /Ca2+ exchanger (NCX) and mitochondria play a role in regulating intracellular Ca2+ homeostasis in the rat SCN neurons. Here we present evidence to show differential regulation by NCX and mitochondria of nimodipine-sensitive and -insensitive Ca2+ influx. METHODS: Ratiometric Ca2+ imaging was used to measure change in [Ca2+ ]i and patch clamp recordings to study spontaneous firing, membrane potential, and voltage-dependent Ca2+ channels in neurons from reduced SCN slice preparations...
May 22, 2018: Journal of Biomedical Science
https://www.readbyqxmd.com/read/29787770/lateral-hypothalamic-orexin-glucose-inhibited-neurons-may-regulate-reward-based-feeding-by-modulating-glutamate-transmission-in-the-ventral-tegmental-area
#3
Suraj B Teegala, Zhenyu Sheng, Miloni S Dalal, Pamela R Hirschberg, Kevin D Beck, Vanessa H Routh
Glucose inhibits ∼60% of lateral hypothalamic (LH) orexin neurons. Fasting increases the activation of LH orexin glucose-inhibited (GI) neurons in low glucose. Increases in spontaneous glutamate excitatory postsynaptic currents (sEPSCs) onto putative VTA DA neurons in low glucose are orexin dependent (Sheng et al., 2014). VTA DA neurons modulate reward-based feeding (Aston-Jones et al., 2010). We tested the hypothesis that increased activation of LH orexin-GI neurons in low glucose increases glutamate signaling onto VTA DA neurons and contributes to reward-based feeding in food restricted animals...
May 19, 2018: Brain Research
https://www.readbyqxmd.com/read/29782051/the-novel-sodium-channel-modulator-gs-458967-gs967-is-an-effective-treatment-in-a-mouse-model-of-scn8a-encephalopathy
#4
Erin M Baker, Christopher H Thompson, Nicole A Hawkins, Jacy L Wagnon, Eric R Wengert, Manoj K Patel, Alfred L George, Miriam H Meisler, Jennifer A Kearney
OBJECTIVE: De novo mutations of SCN8A, encoding the voltage-gated sodium channel NaV 1.6, have been associated with a severe infant onset epileptic encephalopathy. Individuals with SCN8A encephalopathy have a mean age of seizure onset of 4-5 months, with multiple seizure types that are often refractory to treatment with available drugs. Anecdotal reports suggest that high-dose phenytoin is effective for some patients, but there are associated adverse effects and potential for toxicity...
May 21, 2018: Epilepsia
https://www.readbyqxmd.com/read/29782004/levator-auris-longus-preparation-for-examination-of-mammalian-neuromuscular-transmission-under-voltage-clamp-conditions
#5
Steven R A Burke, Eric J Reed, Shannon H Romer, Andrew A Voss
This protocol describes a technique to record synaptic transmission from the neuromuscular junction under current-clamp and voltage-clamp conditions. An ex vivo preparation of the levator auris longus (LAL) is used because it is a thin muscle that provides easy visualization of the neuromuscular junction for microelectrode impalement at the motor endplate. This method allows for the recording of spontaneous miniature endplate potentials and currents (mEPPs and mEPCs), nerve-evoked endplate potentials and currents (EPPs and EPCs), as well as the membrane properties of the motor endplate...
May 5, 2018: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/29781517/a-homozygous-scn5a-mutation-associated-with-atrial-standstill-and-sudden-death
#6
Reina Bianca Tan, Ivan Gando, Lei Bu, Frank Cecchin, William Coetzee
BACKGROUND: Atrial standstill is an arrhythmogenic condition characterized by the absence of spontaneous electrical and mechanical atrial activity or in response to stimulation. There are few reported familial cases which have been associated with SCN5A mutations co-segregating with GJA5 or RYR2 however isolated SCN5A mutations are rare. OBJECTIVE: The purpose of this study was to determine the clinical and biophysical consequence of a novel SCN5A mutation identified in a family with progressive atrial standstill and sudden death...
May 21, 2018: Pacing and Clinical Electrophysiology: PACE
https://www.readbyqxmd.com/read/29778719/effect-of-heptanol-and-ethanol-on-excitation-wave-propagation-in-a-neonatal-rat-ventricular-myocyte-monolayer
#7
A D Podgurskaya, V A Tsvelaya, S R Frolova, I Y Kalita, N N Kudryashova, K I Agladze
In this work, the action of heptanol and ethanol was investigated in a two-dimensional (2D) model of cardiac tissue: the neonatal rat ventricular myocyte monolayer. Heptanol is known in electrophysiology as a gap junction uncoupler but may also inhibit voltage-gated ionic channels. Ethanol is often associated with the occurrence of arrhythmias. These substances influence sodium, calcium, and potassium channels, but the complete mechanism of action of heptanol and ethanol remains unknown. The optical mapping method was used to measure conduction velocities (CVs) in concentrations of 0...
May 17, 2018: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/29777691/improving-electrical-properties-of-ipsc-cardiomyocytes-by-enhancing-cx43-expression
#8
Valentin Sottas, Carl-Mattheis Wahl, Mihnea C Trache, Michael Bartolf-Kopp, Sidney Cambridge, Markus Hecker, Nina D Ullrich
The therapeutic potential of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) is limited by immature functional features including low impulse propagation and reduced cell excitability. Key players regulating electrical activity are voltage-gated Na+ channels (Nav 1.5) and gap junctions built from connexin-43 (Cx43). Here we tested the hypothesis that enhanced Cx43 expression increases intercellular coupling and influences excitability by modulating Nav 1.5. Using transgenic approaches, Cx43 and Nav 1...
May 16, 2018: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/29769426/effect-of-the-intracellular-calcium-concentration-chelator-bapta-acetoxy-methylester-on-action-potential-duration-in-canine-ventricular-myocytes
#9
B Horvath, N Szentandrassy, R Veress, D Baranyai, K Kistamas, J Almassy, A Toth, J Magyar, T Banyasz, P P Nanasi
Intracellular calcium concentration ([Ca2+ ]i ) is often buffered by using the cell-permeant acetoxy-methylester form of the Ca2+ chelator BAPTA (BAPTA-AM) under experimental conditions. This study was designed to investigate the time-dependent actions of extracellularly applied BAPTA-AM on action potential duration (APD) in cardiac cells. Action potentials were recorded from enzymatically isolated canine ventricular myocytes with conventional sharp microelectrodes. The effect of BAPTA-AM on the rapid delayed rectifier K+ current (IKr ) was studied using conventional voltage clamp and action potential voltage clamp techniques...
February 2018: Journal of Physiology and Pharmacology: An Official Journal of the Polish Physiological Society
https://www.readbyqxmd.com/read/29769222/transient-outward-k-current-i-to-underlies-the-right-ventricular-initiation-of-polymorphic-ventricular-tachycardia-in-a-transgenic-rabbit-model-of-long-qt-syndrome-type-1
#10
Bum-Rak Choi, Weiyan Li, Dmitry Terentyev, Anatoli Y Kabakov, Mingwang Zhong, Colin M Rees, Radmila Terentyeva, Tae Yun Kim, Zhilin Qu, Xuwen Peng, Alain Karma, Gideon Koren
BACKGROUND: Sudden death in long-QT syndrome type 1 (LQT1), an inherited disease caused by loss-of-function mutations in KCNQ1, is triggered by early afterdepolarizations (EADs) that initiate polymorphic ventricular tachycardia (pVT). We investigated ionic mechanisms that underlie pVT in LQT1 using a transgenic rabbit model of LQT1. METHODS: Optical mapping, cellular patch clamping, and computer modeling were used to elucidate the mechanisms of EADs in transgenic LQT1 rabbits...
June 2018: Circulation. Arrhythmia and Electrophysiology
https://www.readbyqxmd.com/read/29767950/different-benzodiazepines-bind-with-distinct-binding-modes-to-gaba-a-receptors
#11
Alshaimaa A Elgarf, David C B Siebert, Friederike Steudle, Angelika Draxler, Guanguan Li, Shengming Huang, James M Cook, Margot Ernst, Petra Scholze
Benzodiazepines are clinically relevant drugs, which bind to GABAA neurotransmitter receptors at the α+/γ2- interfaces and thereby enhance GABA induced chloride ion flux leading to neuronal hyperpolarization. However, the structural basis of benzodiazepine interactions with their high affinity site at GABAA receptors is controversially debated in the literature and in silico studies led to discrepant binding mode hypotheses. In the current study computational docking of diazepam into α+/γ2- homology models suggested that a chiral methyl group, which is known to promote preferred binding to α5-containing GABAA receptors (position 3 of the 7-membered diazepine ring), could possibly provide experimental evidence in favor of or against the so far proposed binding modes...
May 16, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29758359/probing-flecainide-block-of-i-na-using-human-pluripotent-stem-cell-derived-ventricular-cardiomyocytes-adapted-to-automated-patch-clamping-and-2d-monolayers
#12
Lin Geng, Chi-Wing Kong, Andy O T Won, Angie Man-Yee Shum, Maggie Z Y Chow, Hui Che, Chenzi Zhang, Ka-Long Yau, Camie W Chan, Wendy Keung, Ronald A Li
Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are emerging tools for applications such as drug discovery and screening for pro-arrhythmogenicity and cardiotoxicity as leading causes for drug attrition. Understanding the electrophysiology (EP) of hPSC-CMs is essential but conventional manual patch-clamping is highly laborious and low-throughput. Here we adapted hPSC-CMs derived from two human embryonic stem cell (hESC) lines, HES2 and H7, for a 16-channel automated planar-recording approach for single-cell EP characterization...
May 11, 2018: Toxicology Letters
https://www.readbyqxmd.com/read/29755973/identification-of-loop-d-domain-amino-acids-in-the-human-aquaporin-1-channel-involved-in-activation-of-the-ionic-conductance-and-inhibition-by-aqb011
#13
Mohamad Kourghi, Michael L De Ieso, Saeed Nourmohammadi, Jinxin V Pei, Andrea J Yool
Aquaporins are integral proteins that facilitate the transmembrane transport of water and small solutes. In addition to enabling water flux, mammalian Aquaporin-1 (AQP1) channels activated by cyclic GMP can carry non-selective monovalent cation currents, selectively blocked by arylsulfonamide compounds AqB007 (IC50 170 μM) and AqB011 (IC50 14 μM). In silico models suggested that ligand docking might involve the cytoplasmic loop D (between AQP1 transmembrane domains 4 and 5), but the predicted site of interaction remained to be tested...
2018: Frontiers in Chemistry
https://www.readbyqxmd.com/read/29753045/identification-and-functional-characterization-of-zebrafish-k-2p-17-1-task-4-talk-2-two-pore-domain-k-channels
#14
Ingo Staudacher, Claudius Illg, Jakob Gierten, Sebastian Seehausen, Patrick A Schweizer, Hugo A Katus, Dierk Thomas
Human K2P 17.1 (TASK-4, TALK-2) two-pore-domain potassium (K2P ) channels have recently been implicated in heart rhythm disorders including atrial fibrillation and conduction disease. The functional in vivo significance of K2P 17.1 currents in cardiac electrophysiology remains incompletely understood. Danio rerio (zebrafish) may be utilized to elucidate the role of cardiac K2P channels in vivo. The aim of this work was to identify and characterize the zebrafish ortholog of K2P 17.1 in comparison to its human counterpart...
May 9, 2018: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29752983/orexin-b-modulates-spontaneous-excitatory-and-inhibitory-transmission-in-lamina-ii-neurons-of-adult-rat-spinal-cord
#15
Chong Wang, Tsugumi Fujita, Eiichi Kumamoto
Cellular mechanisms underlying the antinociceptive properties of orexins, a group of neuropeptides produced by the hypothalamus, in the spinal dorsal horn have not been thoroughly investigated. We examined how orexin B affects spontaneous synaptic transmission in lamina II neurons, which play a pivotal role in regulating nociceptive transmission, by applying a whole-cell patch-clamp technique to lamina II neurons in adult rat spinal cord slices. In 66% of neurons tested, bath-applied orexin B concentration-dependently produced an inward current at -70 mV and/or increased the frequency of glutamatergic spontaneous excitatory postsynaptic current (sEPSC) without changing its amplitude, in a manner resistant to the voltage-gated Na+ -channel blocker tetrodotoxin...
May 9, 2018: Neuroscience
https://www.readbyqxmd.com/read/29752375/functional-invalidation-of-putative-sudden-infant-death-syndrome-associated-variants-in-the-kcnh2-encoded-kv11-1-channel
#16
Jennifer L Smith, David J Tester, Allison R Hall, Don E Burgess, Chun-Chun Hsu, Samy Claude Elayi, Corey L Anderson, Craig T January, Jonathan Z Luo, Dustin N Hartzel, Uyenlinh L Mirshahi, Michael F Murray, Tooraj Mirshahi, Michael J Ackerman, Brian P Delisle
BACKGROUND: Heterologous functional validation studies of putative long-QT syndrome subtype 2-associated variants clarify their pathological potential and identify disease mechanism(s) for most variants studied. The purpose of this study is to clarify the pathological potential for rare nonsynonymous KCNH2 variants seemingly associated with sudden infant death syndrome. METHODS: Genetic testing of 292 sudden infant death syndrome cases identified 9 KCNH2 variants: E90K, R181Q, A190T, G294V, R791W, P967L, R1005W, R1047L, and Q1068R...
May 2018: Circulation. Arrhythmia and Electrophysiology
https://www.readbyqxmd.com/read/29750015/symmetric-dimeric-adamantanes-for-exploring-the-structure-of-two-viroporins-influenza-virus-m2-and-hepatitis-c-virus-p7
#17
Yasmine M Mandour, Ulrike Breitinger, Chunlong Ma, Jun Wang, Frank M Boeckler, Hans-Georg Breitinger, Darius P Zlotos
Background: Adamantane-based compounds have been identified to interfere with the ion-channel activity of viroporins and thereby inhibit viral infection. To better understand the difference in the inhibition mechanism of viroporins, we synthesized symmetric dimeric adamantane analogs of various alkyl-spacer lengths. Methods: Symmetric dimeric adamantane derivatives were synthesized where two amantadine or rimantadine molecules were linked by various alkyl-spacers...
2018: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/29748580/modulation-of-sympathetic-preganglionic-neuron-activity-via-adrenergic-receptors
#18
Yoshino Minoura, Hiroshi Onimaru, Kamon Iigaya, Youichi Kobayashi
The sympathetic preganglionic neurons (SPNs) play a key role in the sympathetic nervous system. Previous reports have suggested that norepinephrine (NE) directly affects SPNs via both inhibitory hyperpolarization interactions mediated by α2 receptors and excitatory depolarization interactions mediated by α1 receptors. It remains poorly understood, however, whether the excitability of SPNs can be inhibited indirectly (presynaptically) as well as directly (postsynaptically). We intracellularly recorded 41 SPNs using the whole-cell patch-clamp technique in spinal cord slice preparations of neonatal rats...
May 10, 2018: Hypertension Research: Official Journal of the Japanese Society of Hypertension
https://www.readbyqxmd.com/read/29747744/yokukansan-contains-compounds-that-antagonize-the-5-ht-3-receptor
#19
Yukiko Nakamura, Yusuke Ishida, Makoto Kondo, Shoichi Shimada
BACKGROUND: We recently focused on alkaloids in Uncaria hook (a constituent of the Kampo medicine, yokukansan) and identified the pharmacological action of geissoschizine methyl ether on several G protein-coupled receptors. However, the functions of other identified alkaloids in Uncaria hook, including hirsutine, hirsuteine, rhynchophylline, isorhynchophylline, corynoxeine, isocorynoxeine, are not clear. PURPOSE: To evaluate the effect of seven alkaloids in Uncaria hook (hirsutine, hirsuteine, rhynchophylline, isorhynchophylline, corynoxeine, isocorynoxeine and geissoschizine methyl ether) on the hydroxytryptamine type-3 (5-HT3 ) receptor ion channel...
April 1, 2018: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://www.readbyqxmd.com/read/29747396/beta-estradiol-regulates-voltage-gated-calcium-channels-and-estrogen-receptors-in-telocytes-from-human-myometrium
#20
Adela Banciu, Daniel Dumitru Banciu, Cosmin Catalin Mustaciosu, Mihai Radu, Dragos Cretoiu, Junjie Xiao, Sanda Maria Cretoiu, Nicolae Suciu, Beatrice Mihaela Radu
Voltage-gated calcium channels and estrogen receptors are essential players in uterine physiology, and their association with different calcium signaling pathways contributes to healthy and pathological conditions of the uterine myometrium. Among the properties of the various cell subtypes present in human uterine myometrium, there is increasing evidence that calcium oscillations in telocytes (TCs) contribute to contractile activity and pregnancy. Our study aimed to evaluate the effects of beta-estradiol on voltage-gated calcium channels and estrogen receptors in TCs from human uterine myometrium and to understand their role in pregnancy...
May 9, 2018: International Journal of Molecular Sciences
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