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https://www.readbyqxmd.com/read/29470055/unique-molecular-regulation-of-higher-order-prefrontal-cortical-circuits-insights-into-the-neurobiology-of-schizophrenia
#1
Dibyadeep Datta, Amy F T Arnsten
Schizophrenia is associated with core deficits in cognitive abilities and impaired functioning of the newly evolved prefrontal association cortex (PFC). In particular, neuropathological studies of schizophrenia have found selective atrophy of the pyramidal cell microcircuits in deep layer III of the dorsolateral PFC (dlPFC), and compensatory weakening of related GABAergic interneurons. Studies in monkeys have shown that recurrent excitation in these layer III microcircuits generates the precisely patterned, persistent firing needed for working memory and abstract thought...
February 22, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29468176/inhibition-of-the-potassium-channel-kv1-3-reduces-infarction-and-inflammation-in-ischemic-stroke
#2
Yi-Je Chen, Hai M Nguyen, Izumi Maezawa, Lee-Way Jin, Heike Wulff
Objective: Inhibitors of the voltage-gated K+ channel Kv1.3 are currently in development as immunomodulators for the treatment of autoimmune diseases. As Kv1.3 is also expressed on microglia and has been shown to be specifically up-regulated on "M1-like" microglia, we here tested the therapeutic hypothesis that the brain-penetrant small-molecule Kv1.3-inhibitor PAP-1 reduces secondary inflammatory damage after ischemia/reperfusion. Methods: We studied microglial Kv1...
February 2018: Annals of Clinical and Translational Neurology
https://www.readbyqxmd.com/read/29467898/anticancer-effect-of-mir-96-inhibitor-in-bladder-cancer-cell-lines
#3
Ting Xu, Xiao-Wen Du, Jun-Biao Hu, Yong-Feng Zhu, Hui-Ling Wu, Guo-Ping Dai, Yao-Min Shu, Jun Ouyang
The present study aimed to investigate the role of microRNA-96 (miR-96) in the proliferation, invasion and apoptosis of bladder cancer cell lines, and the associated mechanisms. The expression of miR-96 and human ether-à- go-go -related (HERG1) potassium channel in the normal uroepithelium SV-HUC-1 cell line, and bladder cancer T24 and 5637 cell lines were examined using reverse transcription-polymerase chain reaction or/and western blotting. Transfection with miR-96 inhibitor or scrambled control (SC) was used to study the biological activities of miR-96 in bladder cancer cell lines...
March 2018: Oncology Letters
https://www.readbyqxmd.com/read/29467644/use-of-peptides-for-the-management-of-alzheimer-s-disease-diagnosis-and-inhibition
#4
REVIEW
Mohammad H Baig, Khurshid Ahmad, Gulam Rabbani, Inho Choi
Alzheimer's disease (AD) is a form of dementia and the most common progressive neurodegenerative disease (ND). The targeting of amyloid-beta (Aβ) aggregation is one of the most widely used strategies to manage AD, and efforts are being made globally to develop peptide-based compounds for the early diagnosis and treatment of AD. Here, we briefly discuss the use of peptide-based compounds for the early diagnosis and treatment of AD and the use of peptide-based inhibitors targeting various Aβ aggregation checkpoints...
2018: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/29467578/cholesterol-binding-sites-in-girk-channels-the-devil-is-in-the-details
#5
Avia Rosenhouse-Dantsker
In recent years, it has become evident that cholesterol plays a direct role in the modulation of a variety of ion channels. In most cases, cholesterol downregulates channel activity. In contrast, our earlier studies have demonstrated that atrial G protein inwardly rectifying potassium (GIRK) channels are upregulated by cholesterol. Recently, we have shown that hippocampal GIRK currents are also upregulated by cholesterol. A combined computational-experimental approach pointed to putative cholesterol-binding sites in the transmembrane domain of the GIRK2 channel, the primary subunit in hippocampal GIRK channels...
2018: Lipid Insights
https://www.readbyqxmd.com/read/29466724/bk-potassium-channels-suppress-cav%C3%AE-2%C3%AE-subunit-function-to-reduce-inflammatory-and-neuropathic-pain
#6
Fang-Xiong Zhang, Vinicius M Gadotti, Ivana A Souza, Lina Chen, Gerald W Zamponi
Cavα2δ subunits contribute to the cell-surface expression of Cav2 calcium channels. Upregulation of Cavα2δ-1 in dorsal root ganglion neurons occurs after nerve injury and results in an increased synaptic abundance of Cav2.2 channels in the spinal dorsal horn, thus enhancing the transmission of pain signals. Here, we report that large conductance calcium-activated potassium (BK) channels interact with the Cavα2δ subunit. Coexpression of BK channels with the Cav2 calcium channels reduces their cell-surface expression and whole-cell current density by competing the Cavα2δ subunit away from the Cav2 complex...
February 20, 2018: Cell Reports
https://www.readbyqxmd.com/read/29466671/lipopolysaccharide-stimulates-bk-channel-activity-in-bladder-umbrella-cells
#7
Ming Lu, Jian-Ri Li, Lery Alvarez-Lugo, Yan Li, Shan Yu, Xuanhao Li, Benkang Shi, Toby C Chai
Bladder urothelium plays an active role in response to bacterial infection. There is little known about the electrophysiological activity in urothelial cells in this process. We used a non-enzymatic method to isolate bladder urothelial tissue and to patch clamp umbrella cells in situ. A 200pS conductance potassium (K+ ) channel was detected from female C57BL6 mice. Of 58 total patches, 17.2% patches displayed the 200pS K+ conductance channel. This K+ conductance channel showed Ca2+ sensitivity and voltage dependence...
February 21, 2018: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/29464848/corm-401-induces-calcium-signalling-no-increase-and-activation-of-pentose-phosphate-pathway-in-endothelial-cells
#8
Patrycja Kaczara, Bartosz Proniewski, Christopher Lovejoy, Kamil Kuś, Roberto Motterlini, Andrey Y Abramov, Stefan Chlopicki
Carbon monoxide-releasing molecules (CO-RMs) induce nitric oxide (NO) release (which requires NADPH), and Ca2+ -dependent signalling; however, their contribution in mediating endothelial responses is not clear. Here, we studied the effects of CO liberated from CORM-401 on NO production, calcium signalling and pentose phosphate pathway (PPP) activity in human endothelial cell line (EA.hy926). CORM-401 induced NO production and two types of calcium signalling: a peak-like calcium signal and a gradual increase in cytosolic calcium...
February 21, 2018: FEBS Journal
https://www.readbyqxmd.com/read/29464397/mining-protein-evolution-for-insights-into-mechanisms-of-voltage-dependent-sodium-channel-auxiliary-subunits
#9
Steven Molinarolo, Daniele Granata, Vincenzo Carnevale, Christopher A Ahern
Voltage-gated sodium channel (VGSC) beta (β) subunits have been called the "overachieving" auxiliary ion channel subunit. Indeed, these subunits regulate the trafficking of the sodium channel complex at the plasma membrane and simultaneously tune the voltage-dependent properties of the pore-forming alpha-subunit. It is now known that VGSC β-subunits are capable of similar modulation of multiple isoforms of related voltage-gated potassium channels, suggesting that their abilities extend into the broader voltage-gated channels...
February 21, 2018: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/29464270/diabetes-modifies-the-role-of-prostanoids-and-potassium-channels-which-regulate-the-hypereactivity-of-the-rabbit-renal-artery-to-bnp
#10
José M Centeno, Luis Miranda-Gómez, Mikahela A López-Morales, Teresa Jover-Mengual, María C Burguete, Vannina G Marrachelli, María Castelló-Ruiz, Alicia Aliena-Valero, Enrique Alborch, Francisco J Miranda
Diabetic nephropathy is associated with increased risk of cardiovascular disease. B-type natriuretic peptide (BNP) plays an important role in cardiovascular pathophysiology and therapeutics. The aim of the present study was to investigate the influence of experimental diabetes on the mechanisms that regulate the relaxant response of the rabbit renal artery to BNP. Arterial relaxations to BNP were enhanced in diabetic rabbits. Indomethacin enhanced BNP-induced relaxation in control rabbits but showed no effect in diabetic rabbits...
February 21, 2018: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/29464197/mecp2-deficiency-leads-to-loss-of-glial-kir4-1
#11
Uri Kahanovitch, Vishnu A Cuddapah, Natasha L Pacheco, Leanne M Holt, Daniel K Mulkey, Alan K Percy, Michelle L Olsen
Rett syndrome (RTT) is an X-linked neurodevelopmental disorder usually caused by mutations in methyl-CpG-binding protein 2 (MeCP2). RTT is typified by apparently normal development until 6-18 mo of age, when motor and communicative skills regress and hand stereotypies, autonomic symptoms, and seizures present. Restoration of MeCP2 function selectively to astrocytes reversed several deficits in a murine model of RTT, but the mechanism of this rescue is unknown. Astrocytes carry out many essential functions required for normal brain functioning, including extracellular K+ buffering...
January 2018: ENeuro
https://www.readbyqxmd.com/read/29463953/autosomal-dominant-retinitis-pigmentosa-rhodopsin-mutant-q344x-drives-specific-alterations-in-chromatin-complex-gene-transcription
#12
Katie L Bales, Lara Ianov, Andrew J Kennedy, J David Sweatt, Alecia K Gross
Purpose: Epigenetic and transcriptional mechanisms have been shown to contribute to long-lasting functional changes in adult neurons. The purpose of this study was to identify any such modifications in diseased retinal tissues from a mouse model of rhodopsin mutation-associated autosomal dominant retinitis pigmentosa (ADRP), Q344X, relative to age-matched wild-type (WT) controls. Methods: We performed RNA sequencing (RNA-seq) at poly(A) selected RNA to profile the transcriptional patterns in 3-week-old ADRP mouse model rhodopsin Q344X compared to WT controls...
2018: Molecular Vision
https://www.readbyqxmd.com/read/29462682/modulation-of-kv3-1b-potassium-channel-level-and-intracellular-potassium-concentration-in-158n-murine-oligodendrocytes-and-bv-2-murine-microglial-cells-treated-with-7-ketocholesterol-24s-hydroxycholesterol-or-tetracosanoic-acid-c24-0
#13
Maryem Bezine, Sonia Maatoug, Rym Ben Khalifa, Meryam Debbabi, Amira Zarrouk, Yuqin Wang, William J Griffiths, Thomas Nury, Mohammad Samadi, Anne Vejux, Jérôme de Sèze, Thibault Moreau, Riadh Kharrat, Mohamed El Ayeb, Gérard Lizard
Little is known about K+ regulation playing major roles in the propagation of nerve impulses, as well as in apoptosis and inflammasome activation involved in neurodegeneration. As increased levels of 7-ketocholesterol (7KC), 24S-hydroxycholesterol (24S-OHC) and tetracosanoic acid (C24:0) have been observed in patients with neurodegenerative diseases, we studied the effect of 24 and/or 48 h of treatment with 7KC, 24S-OHC and C24:0 on Kv3.1b potassium channel level, intracellular K+ concentration, oxidative stress, mitochondrial dysfunction, and plasma membrane permeability in 158N oligodendrocytes and BV-2 microglial cells...
February 17, 2018: Biochimie
https://www.readbyqxmd.com/read/29460236/a-double-blind-randomised-placebo-controlled-cross-over-study-assessing-the-use-of-xen-d0103-in-patients-with-paroxysmal-atrial-fibrillation-and-implanted-pacemakers-allowing-continuous-beat-to-beat-monitoring-of-drug-efficacy
#14
S R Shunmugam, Conn Sugihara, Nick Freemantle, Patrick Round, Steve Furniss, Neil Sulke
PURPOSE: The ultrarapid delayed rectifier current (IKur ) carried by Kv1.5 channels, which are solely expressed in the atrium, is a potential target for safer treatment of paroxysmal atrial fibrillation (PAF). XEN-D0103 is a nanomolar ion channel blocker that selectively inhibits potassium ion flux through the Kv1.5 ion channel. The efficacy of XEN-D0103 in reducing AF burden was assessed in patients with DDDRp permanent pacemakers (PPMs) and PAF. METHODS: A double-blind, placebo-controlled, cross-over study was performed in patients with PAF and DDDRp PPMs with advanced atrial and ventricular Holters allowing beat-to-beat arrhythmia follow-up...
February 19, 2018: Journal of Interventional Cardiac Electrophysiology: An International Journal of Arrhythmias and Pacing
https://www.readbyqxmd.com/read/29460173/changes-in-the-axo-glial-junctions-of-the-optic-nerves-of-cuprizone-treated-mice
#15
Wataru Kojima, Kensuke Hayashi
Demyelination induced by cuprizone in mice has served a useful model system for the study of demyelinating diseases, such as multiple sclerosis. Severity of demyelination by cuprizone, however, varies across different regions of the central nervous system; the corpus callosum is sensitive, while the optic nerves are resistant. Here, we investigated the effects of cuprizone on optic nerves, focusing on the axo-glial junctions. Immunostaining for sodium channels, contactin-associated protein, neurofascins, and potassium channels revealed that there were no massive changes in the density and morphology of the axo-glial junctions in cuprizone-treated optic nerves...
February 19, 2018: Histochemistry and Cell Biology
https://www.readbyqxmd.com/read/29459730/a-single-nak-channel-conformation-is-not-enough-for-non-selective-ion-conduction
#16
Chaowei Shi, Yao He, Kitty Hendriks, Bert L de Groot, Xiaoying Cai, Changlin Tian, Adam Lange, Han Sun
NaK and other non-selective channels are able to conduct both sodium (Na+ ) and potassium (K+ ) with equally high efficiency. In contrast to previous crystallographic results, we show that the selectivity filter (SF) of NaK in native-like lipid membranes adopts two distinct conformations that are stabilized by either Na+ or K+ ions. The atomic differences of these conformations are resolved by solid-state NMR (ssNMR) spectroscopy and molecular dynamics (MD) simulations. Besides the canonical K+ permeation pathway, we identify a side entry ion-conduction pathway for Na+ permeation unique to NaK...
February 19, 2018: Nature Communications
https://www.readbyqxmd.com/read/29458000/evidence-for-a-mitochondrial-atp-regulated-potassium-channel-in-human-dermal-fibroblasts
#17
Piotr Bednarczyk, Anna Kicinska, Michal Laskowski, Bogusz Kulawiak, Rafal Kampa, Agnieszka Walewska, Milena Krajewska, Wieslawa Jarmuszkiewicz, Adam Szewczyk
Mitochondrial ATP-regulated potassium channels are present in the inner membrane of the mitochondria of various cells. In the present study, we show for the first time mitochondrial ATP-regulated potassium channels in human dermal fibroblast cells. Using the patch-clamp technique on the inner mitochondrial membrane of fibroblasts, we detected a potassium channel with a mean conductance equal to 100 pS in symmetric 150 mM KCl. The activity of this channel was inhibited by a complex of ATP/Mg2+ and activated by potassium channel openers such as diazoxide or BMS 191095...
February 16, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29456831/early-afterdepolarisation-tendency-as-a-simulated-pro-arrhythmic-risk-indicator
#18
Beth McMillan, David J Gavaghan, Gary R Mirams
Drug-induced Torsades de Pointes (TdP) arrhythmia is of major interest in predictive toxicology. Drugs which cause TdP block the hERG cardiac potassium channel. However, not all drugs that block hERG cause TdP. As such, further understanding of the mechanistic route to TdP is needed. Early afterdepolarisations (EADs) are a cell-level phenomenon in which the membrane of a cardiac cell depolarises a second time before repolarisation, and EADs are seen in hearts during TdP. Therefore, we propose a method of predicting TdP using induced EADs combined with multiple ion channel block in simulations using biophysically-based mathematical models of human ventricular cell electrophysiology...
November 1, 2017: Toxicology Research
https://www.readbyqxmd.com/read/29456800/discovery-and-in-vitro-optimization-of-3-sulfamoylbenzamides-as-romk-inhibitors
#19
Matthew F Sammons, Sujay V Kharade, Kevin J Filipski, Markus Boehm, Aaron C Smith, Andre Shavnya, Dilinie P Fernando, Matthew S Dowling, Philip A Carpino, Neil A Castle, Shannon G Zellmer, Brett M Antonio, James R Gosset, Anthony Carlo, Jerod S Denton
Inhibitors of the renal outer medullary potassium channel (ROMK) show promise as novel mechanism diuretics, with potentially lower risk of diuretic-induced hypokalemia relative to current thiazide and loop diuretics. Here, we report the identification of a novel series of 3-sulfamoylbenzamide ROMK inhibitors. Starting from HTS hit 4 , this series was optimized to provide ROMK inhibitors with good in vitro potencies and well-balanced ADME profiles. In contrast to previously reported small-molecule ROMK inhibitors, members of this series were demonstrated to be highly selective for inhibition of human over rat ROMK and to be insensitive to the N171D pore mutation that abolishes inhibitory activity of previously reported ROMK inhibitors...
February 8, 2018: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29453198/targeting-kca1-1-channels-with-a-scorpion-venom-peptide-for-the-therapy-of-rat-models-of-rheumatoid-arthritis
#20
Mark R Tanner, Michael W Pennington, Brayden H Chamberlain, Redwan Huq, Elizabeth J Gehrmann, Teresina Laragione, Percio S Gulko, Christine Beeton
Fibroblast-like synoviocytes (FLS) are a key cell-type involved in rheumatoid arthritis (RA) progression. We previously identified the KCa1.1 potassium channel (Maxi-K, BK, Slo 1, KCNMA1) as a regulator of FLS and that KCa1.1 inhibition reduces disease severity in RA animal models. However, systemic KCa1.1 block causes multiple side effects and in this study, we aimed to determine whether the KCa1.1 β1-3-specific venom peptide blocker iberiotoxin (IbTX) reduces disease severity in animal models of RA without inducing major side effects...
February 16, 2018: Journal of Pharmacology and Experimental Therapeutics
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