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https://www.readbyqxmd.com/read/28212175/advances-in-epilepsy-gene-discovery-and-implications-for-epilepsy-diagnosis-and-treatment
#1
Joseph D Symonds, Sameer M Zuberi, Michael R Johnson
PURPOSE OF REVIEW: Epilepsy genetics is shifting from the academic pursuit of gene discovery to a clinical discipline based on molecular diagnosis and stratified medicine. We consider the latest developments in epilepsy genetics and review how gene discovery in epilepsy is influencing the clinical classification of epilepsy and informing new therapeutic approaches and drug discovery. RECENT FINDINGS: Recent studies highlighting the importance of mutation in GABA receptors, NMDA receptors, potassium channels, G-protein coupled receptors, mammalian target of rapamycin pathway and chromatin remodeling are discussed...
February 15, 2017: Current Opinion in Neurology
https://www.readbyqxmd.com/read/28211063/gating-energetics-of-a-voltage-dependent-k-channel-pore-domain
#2
Greg Starek, J Alfredo Freites, Simon Bernèche, Douglas J Tobias
We used targeted molecular dynamics, informed by experimentally determined inter-atomic distances defining the pore region of open and closed states of the KvAP voltage-gated potassium channel, to generate a gating pathway of the pore domain in the absence of the voltage-sensing domains. We then performed umbrella sampling simulations along this pathway to calculate a potential of mean force that describes the free energy landscape connecting the closed and open conformations of the pore domain. The resulting energetic landscape displays three minima, corresponding to stable open, closed, and intermediate conformations with roughly similar stabilities...
February 16, 2017: Journal of Computational Chemistry
https://www.readbyqxmd.com/read/28209036/-primary-culture-and-functional-identification-of-distal-pulmonary-artery-smooth-muscle-cells-in-mice
#3
M C Li, Y Q Chen, C T Zhang, Q Jiang, W J Lu, J Wang
Objective: To establish a method of isolation and primary culture of mice distal pulmonary artery smooth muscle cells (PASMCs) and identify the functional properties. Methods: PASMCs were harvested from the distal pulmonary artery (PA) tissue of mice by enzymatic digestion of collagenaseⅠand papain; and the growth characteristics were observed under inverted microscope and identified by Immunofluorescence technique. Effects on the intracellular calcium ion concentration of distal PASMCs were detected by Fura-2-AM fluorescent probe tracer under a fluorescence microscope in Krebs solution containing clopiazonic acid (CPA) and nifedipin (Nif)...
February 12, 2017: Chinese Journal of Tuberculosis and Respiratory Diseases
https://www.readbyqxmd.com/read/28208271/cation-dependent-surface-charge-regulation-in-gated-nanofluidic-devices
#4
Marie Fuest, Kaushik K Rangharajan, Caitlin Boone, A T Conlisk, Shaurya Prakash
Surface charge governs nanoscale aqueous electrolyte transport, both in engineered analytical systems and in biological entities such as ion channels and ion pumps as a function of ion type and concentration. Embedded electrodes in a nanofluidic channel, isolated from the fluid in the channel by a dielectric layer, act as active, tunable gates to systematically modify local surface charge density at the interface between the nanochannel surface and the aqueous electrolyte solution, causing significant changes in measured nanochannel conductance...
February 7, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28205094/knockdown-of-cardiac-kir3-1-gene-with-sirna-can-improve-bradycardia-in-an-experimental-sinus-bradycardia-rat-model
#5
Yang Li, Xiaodan Fu, Zhi Zhang, Bo Yu
The objective of this study was to explore whether the inhibition of potassium inwardly rectifying channel (Kir3.1) with short interfering RNA (siRNA) can improve bradycardia in an experimental sinus bradycardia rat model. 54 Sprague Dawley (SD) rats were randomly divided into three groups: experimental group, control group, and sham group. Sinus bradycardia model was established in SD rats through chemical ablation of sinoatrial (SA) node with 20% formaldehyde. Variations of Kir3.1 expression at mRNA and protein level were examined with qPCR and Western blotting...
February 15, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/28204960/sites-and-functional-consequence-of-alkylphenol-anesthetic-binding-to-kv1-2-channels
#6
Weiming Bu, Qiansheng Liang, Lianteng Zhi, Lina Maciunas, Patrick J Loll, Roderic G Eckenhoff, Manuel Covarrubias
Inhalational general anesthetics, such as sevoflurane and isoflurane, modulate a subset of brain Kv1 potassium channels. However, the Kv1.2 channel is resistant to propofol, a commonly used intravenous alkylphenol anesthetic. We hypothesize that propofol binds to a presumed pocket involving the channel's S4-S5 linker, but functional transduction is poor and, therefore, propofol efficacy is low. To test this hypothesis, we used a photoactive propofol analog (meta-aziPropofol = AziPm) to directly probe binding and electrophysiological and mutational analyses in Xenopus oocytes to probe function...
February 15, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28202576/differential-effect-of-brief-electrical-stimulation-on-voltage-gated-potassium-channels
#7
Morven Alison Cameron, Amr Al Abed, Yossi Buskila, Socrates Dokos, Nigel H Lovell, John W Morley
Electrical stimulation of neuronal tissue is a promising strategy to treat a variety of neurological disorders. The mechanism of neuronal activation by external electrical stimulation is governed by voltage-gated ion channels. This stimulus, typically brief in nature, leads to membrane potential depolarization, which increases ion flow across the membrane by increasing the open probability of these voltage-gated channels. In spiking neurons, it is activation of voltage-gated sodium channels (NaV-channels) that leads to action potential generation...
February 15, 2017: Journal of Neurophysiology
https://www.readbyqxmd.com/read/28198801/inhibitory-effects-of-cholinesterase-inhibitor-donepezil-on-the-kv1-5-potassium-channel
#8
Kai Li, Neng Cheng, Xian-Tao Li
Kv1.5 channels carry ultra-rapid delayed rectifier K(+) currents in excitable cells, including neurons and cardiac myocytes. In the current study, the effects of cholinesterase inhibitor donepezil on cloned Kv1.5 channels expressed in HEK29 cells were explored using whole-cell recording technique. Exposure to donepezil resulted in a rapid and reversible block of Kv1.5 currents, with an IC50 value of 72.5 μM. The mutant R476V significantly reduced the binding affinity of donepezil to Kv1.5 channels, showing the target site in the outer mouth region...
February 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28197922/coordination-of-cellular-localization-dependent-effects-of-sumoylation-in-regulating-cardiovascular-and-neurological-diseases
#9
Jun-Ichi Abe, Uday G Sandhu, Nguyet Minh Hoang, Manoj Thangam, Raymundo A Quintana-Quezada, Keigi Fujiwara, Nhat Tu Le
Sumoylation, a reversible post-transcriptional modification process, of proteins are involved in cellular differentiation, growth, and even motility by regulating various protein functions. Sumoylation is not limited to cytosolic proteins as recent evidence shows that nuclear proteins, those associated with membranes, and mitochondrial proteins are also sumoylated. Moreover, it is now known that sumoylation plays an important role in the process of major human ailments such as malignant, cardiovascular and neurological diseases...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28197715/vacuolar-ion-channels-in-the-liverwort-marchantia-polymorpha-influence-of-ion-channel-inhibitors
#10
Mateusz Koselski, Kazimierz Trebacz, Halina Dziubinska
Potassium-permeable slow activating vacuolar channels (SV) and chloride-permeable channels in the vacuole of the liverwort Marchantia polymorpha were characterized in respect to calcium dependence, selectivity, and pharmacology. The patch-clamp method was used in the study of ion channel activity in the vacuoles from the liverwort Marchantia polymorpha. The whole-vacuole recordings allowed simultaneous observation of two types of currents-predominant slow activated currents recorded at positive voltages and fast activated currents recorded at negative voltages...
February 14, 2017: Planta
https://www.readbyqxmd.com/read/28193892/kv1-1-channelopathy-abolishes-presynaptic-spike-width-modulation-by-subthreshold-somatic-depolarization
#11
Umesh Vivekananda, Pavel Novak, Oscar D Bello, Yuri E Korchev, Shyam S Krishnakumar, Kirill E Volynski, Dimitri M Kullmann
Although action potentials propagate along axons in an all-or-none manner, subthreshold membrane potential fluctuations at the soma affect neurotransmitter release from synaptic boutons. An important mechanism underlying analog-digital modulation is depolarization-mediated inactivation of presynaptic Kv1-family potassium channels, leading to action potential broadening and increased calcium influx. Previous studies have relied heavily on recordings from blebs formed after axon transection, which may exaggerate the passive propagation of somatic depolarization...
February 13, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28192752/genistein-inhibits-hypoxia-ischemic-induced-death-and-apoptosis-in-pc12-cells
#12
Yu-Xiang Wang, Kun Tian, Cong-Cong He, Xue-Ling Ma, Feng Zhang, Hong-Gang Wang, Di An, Bin Heng, Yu-Gang Jiang, Yan-Qiang Liu
A hypoxia/ischemia neuronal model was established in PC12 cells using oxygen-glucose deprivation (OGD). OGD-induced neuronal death, apoptosis, glutamate receptor subunit GluR2 expression, and potassium channel currents were evaluated in the present study to determine the effects of genistein in mediating the neuronal death and apoptosis induced by hypoxia and ischemia, as well as its underlying mechanism. OGD exposure reduced the cell viability, increased apoptosis, decreased the GluR2 expression, and decreased the voltage-activated potassium currents...
February 1, 2017: Environmental Toxicology and Pharmacology
https://www.readbyqxmd.com/read/28192611/deficiency-of-trek-1-potassium-channel-exacerbates-secondary-injury-following-spinal-cord-injury-in-mice
#13
Yongkang Fang, Xiaojiang Huang, Yue Wan, Hao Tian, Yeye Tian, Wei Wang, Suiqiang Zhu, Minjie Xie
Spinal cord injury (SCI) involves complex pathological process which can be complicated by secondary injury. TREK-1 is a member of the two-pore domain potassium (K2P) channel family, which can be modulated by a number of physiological and pathological stimuli. Recent studies suggest that TREK-1 plays an active role in depression, pain and neuroprotection. However, its role in the pathological process after SCI remains unclear. In this study, we tested the expression and function of TREK-1 in spinal cord of mice after traumatic SCI...
February 13, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28192542/functional-diversity-of-secreted-cestode-kunitz-proteins-inhibition-of-serine-peptidases-and-blockade-of-cation-channels
#14
Martín Fló, Mariana Margenat, Leonardo Pellizza, Martín Graña, Rosario Durán, Adriana Báez, Emilio Salceda, Enrique Soto, Beatriz Alvarez, Cecilia Fernández
We previously reported a multigene family of monodomain Kunitz proteins from Echinococcus granulosus (EgKU-1-EgKU-8), and provided evidence that some EgKUs are secreted by larval worms to the host interface. In addition, functional studies and homology modeling suggested that, similar to monodomain Kunitz families present in animal venoms, the E. granulosus family could include peptidase inhibitors as well as channel blockers. Using enzyme kinetics and whole-cell patch-clamp, we now demonstrate that the EgKUs are indeed functionally diverse...
February 13, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28192231/hypotensive-and-vasorelaxant-effect-of-diapocynin-in-normotensive-rats
#15
Simone R Potje, Jéssica A Troiano, Murilo E Graton, Valdecir F Ximenes, Ana Claúdia M S Nakamune, Cristina Antoniali
Nicotinamide adenine dinucleotide phosphate oxidase (NAD(P)H-oxidase) is a multicomponent enzyme system that generates superoxide anion by one-electron reduction of molecular oxygen and represents the major source of reactive oxygen species (ROS) in the vascular cells. Apocynin has been extensively used as an inhibitor of NADPH oxidase (NOX) in phagocytic cells and as an antioxidant in non-phagocytic cells. In phagocytes cells, due to the presence of myeloperoxidase, apocynin can be the converted to diapocynin, which is supposed to be the active form of this phytochemical...
February 9, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28192090/optogenetic-control-of-ca-2-and-voltage-dependent-large-conductance-bk-potassium-channels
#16
Thomas Mager, Phillip G Wood, Ernst Bamberg
Ca(2+) concentration jumps for the activation of Ca(2+) dependent ion channels or transporters can be obtained either by fast solution exchange or the use of caged Ca(2+). Here we report on an alternate optogenetic method for activation of Ca(2+) and voltage dependent large conductance (BK) potassium channels. This was achieved through the use of the light-gated Ca(2+) permeable Channelrhodopsin 2 variant, CatCh, with enhanced Ca(2+) permeability, which produces locally [Ca(2+)] in the μM range on the inner side of the membrane, without significant [Ca(2+)] increase in the cytosol...
February 10, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28188958/potassium-channel-gene-associations-with-joint-processing-speed-and-white-matter-impairments-in-schizophrenia
#17
Heather A Bruce, Peter Kochunov, Sara A Paciga, Craig L Hyde, Xing Chen, Zhiyong Xie, Baohong Zhang, Hualin S Xi, Patricio O'Donnell, Christopher Whelan, Christian R Schubert, Alfredo Bellon, Seth A Ament, Dinesh K Shukla, Xiaoming Du, Laura M Rowland, Hugh O'Neill, L Elliot Hong
Patients with schizophrenia show decreased processing speed on neuropsychological testing and decreased white matter integrity as measured by diffusion tensor imaging, two traits shown to be both heritable and genetically associated indicating that there may be genes that influence both traits as well as schizophrenia disease risk. The potassium channel gene family is a reasonable candidate to harbor such a gene given the prominent role potassium channels play in the central nervous system in signal transduction, particularly in myelinated axons...
February 11, 2017: Genes, Brain, and Behavior
https://www.readbyqxmd.com/read/28188450/terminal-latency-abnormality-in-amyotrophic-lateral-sclerosis-without-split-hand-syndrome
#18
Donghwi Park, Jin-Sung Park
Amyotrophic lateral sclerosis (ALS) has a peculiar involvement pattern; clinically it is known as split hand syndrome and electrophysiologically shows abnormalities in the abductor pollicis brevis (APB)/abductor digiti minimi (ADM) ratio. The aim of this study was to find a significant electrophysiological parameter in upper limb onset ALS patients with normal APB/ADM ratio when compared to cervical spondylotic amyotrophy (CSA) and healthy controls. We retrospectively reviewed the electrophysiological results of 47 upper limb onset ALS and 42 CSA cases; 20 healthy individuals were included as controls...
February 10, 2017: Neurological Sciences
https://www.readbyqxmd.com/read/28188270/dual-mechanism-for-inhibition-of-inwardly-rectifying-kir2-x-channels-by-quinidine-involving-direct-pore-block-and-pip2-interference
#19
Christoph Koepple, Daniel Scherer, Claudia Seyler, Eberhard Scholz, Dierk Thomas, Hugo A Katus, Edgar Zitron
Class IA antiarrhythmic drug quinidine was one of the first clinically used compounds to terminate atrial fibrillation and acts as multichannel inhibitor with well-documented inhibitory effects on several cardiac potassium channels. In the mammalian heart, heteromeric assembly of Kir2.1-2.3 channels underlies IK1 current. While a low-affinity block of quinidine on Kir2.1 has already been described, a comparative analysis of effects on other Kir2.x channels has not been performed to date. Therefore, we analyzed the effects of quinidine on wild type and mutant Kir2...
February 10, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28188005/g-protein-gated-potassium-channels-a-link-to-drug-addiction
#20
REVIEW
Robert A Rifkin, Stephen J Moss, Paul A Slesinger
G protein-gated inwardly rectifying potassium (GIRK) channels are regulators of neuronal excitability in the brain. Knockout mice lacking GIRK channels display altered behavioral responses to multiple addictive drugs, implicating GIRK channels in addictive behaviors. Here, we review the effects of GIRK subunit deletions on the behavioral response to psychostimulants, such as cocaine and methamphetamine. Additionally, exposure of mice to psychostimulants produces alterations in the surface expression of GIRK channels in multiple types of neurons within the reward system of the brain...
February 7, 2017: Trends in Pharmacological Sciences
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