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https://www.readbyqxmd.com/read/28105280/glun2a-selective-pyridopyrimidinone-series-of-nmdar-positive-allosteric-modulators-with-an-improved-in-vivo-profile
#1
Elisia Villemure, Matthew Volgraf, Yu Jiang, Guosheng Wu, Cuong Q Ly, Po-Wai Yuen, Aijun Lu, Xifeng Luo, Mingcui Liu, Shun Zhang, Patrick J Lupardus, Heidi J A Wallweber, Bianca M Liederer, Gauri Deshmukh, Emile Plise, Suzanne Tay, Tzu-Ming Wang, Jesse E Hanson, David H Hackos, Kimberly Scearce-Levie, Jacob B Schwarz, Benjamin D Sellers
The N-methyl-d-aspartate receptor (NMDAR) is an ionotropic glutamate receptor, gated by the endogenous coagonists glutamate and glycine, permeable to Ca(2+) and Na(+). NMDAR dysfunction is associated with numerous neurological and psychiatric disorders, including schizophrenia, depression, and Alzheimer's disease. Recently, we have disclosed GNE-0723 (1), a GluN2A subunit-selective and brain-penetrant positive allosteric modulator (PAM) of NMDARs. This work highlights the discovery of a related pyridopyrimidinone core with distinct structure-activity relationships, despite the structural similarity to GNE-0723...
January 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28102080/n-oleoylglycine-induced-hyperphagia-was-associated-with-the-activation-of-agrp-neuron-by-cb1r
#2
Junguo Wu, Canjun Zhu, Liusong Yang, Zhonggang Wang, Lina Wang, Songbo Wang, Ping Gao, Yongliang Zhang, Qingyan Jiang, Gang Shu, Xiaotong Zhu
N-acyl amino acids (NAAAs) are conjugate products of fatty acids and amino acids, which are available in animal-derived food. We compared the effects of N-arachidonoyl glycine (NAGly), N-arachidonoyl serine (NASer), and N-Oleoylglycine (OLGly) on in vivo food intake and in vitro [Ca2+]i of AgRP neurons to identify the role of these compounds in energy homeostasis. The hypothalamic neuropeptide expression and anxiety behavior in response to OLGly were also tested. To further identify the underlying mechanism of OLGly on food intake, we first detected the expression level of potential OLGly receptors...
January 19, 2017: Journal of Agricultural and Food Chemistry
https://www.readbyqxmd.com/read/28101463/development-of-a-novel-human-single-chain-antibody-against-egfrviii-antigen-by-phage-display-technology
#3
Leila Rahbarnia, Safar Farajnia, Hossein Babaei, Jafar Majidi, Bahman Akbari, Shiva Ahdi Khosroshahi
Purpose: EGFRvIII as the most common mutant variant of the epidermal growth factor receptor is resulting from deletion of exons 2-7 in the coding sequence and junction of exons 1 and 8 through a novel glycine residue. EGFRvIII is highly expressed in glioblastoma, carcinoma of the breast, ovary, and lung but not in normal cells. The aim of the present study was identification of a novel single chain antibody against EGFRvIII as a promising target for cancer therapy. Methods: In this study, a synthetic peptide corresponding to EGFRvIII protein was used for screening a naive human scFv phage library...
December 2016: Advanced Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28096877/efficacy-and-safety-of-bitopertin-in-patients-with-schizophrenia-and-predominant-negative-symptoms-subgroup-analysis-of-japanese-patients-from-the-global-randomized-phase-2-trial
#4
Yoshio Hirayasu, Shin-Ichi Sato, Norifumi Shuto, Miwa Nakano, Teruhiko Higuchi
OBJECTIVE: The aim of the present study was to perform a subgroup analysis of data from a phase II global, multi-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of bitopertin, a glycine reuptake inhibitor that activates N-methyl-D-aspartate receptors by increasing the concentration of glycine in the synaptic cleft, in Japanese and non-Japanese patients with schizophrenia and predominant negative symptoms. METHODS: Patients with schizophrenia and predominant negative symptoms on one or two antipsychotic drugs, including atypical antipsychotic drugs (olanzapine, risperidone, quetiapine, aripiprazole, and paliperidone) as the primary treatment, received bitopertin (10, 30, or 60 mg/day) or placebo once daily for 8 weeks as an add-on treatment...
January 2017: Psychiatry Investigation
https://www.readbyqxmd.com/read/28087784/interactions-between-zinc-and-allosteric-modulators-of-the-glycine-receptor
#5
Garrett L Cornelison, Anna W Daszkowski, Natasha C Pflanz, S John Mihic
The glycine receptor is a pentameric ligand-gated ion channel involved in fast inhibitory neurotransmission in the central nervous system. Zinc is an allosteric modulator of glycine receptor function, enhancing the effects of glycine at nM to low μM concentrations, and inhibiting its effects at higher concentrations. Low nM concentrations of contaminating zinc in electrophysiological buffers are capable of synergistically enhancing receptor modulation by other compounds such as ethanol. This suggests that, unless accounted for, previous studies of glycine receptor modulation were measuring the effects of modulator plus co-modulation by zinc on receptor function...
January 13, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28069702/remote-ischemic-conditioning-provides-humoural-cross-species-cardioprotection-through-glycine-receptor-activation
#6
Juan José Alburquerque-Béjar, Ignasi Barba, Laura Valls-Lacalle, Marisol Ruiz-Meana, Michela Pecoraro, Antonio Rodríguez-Sinovas, David García-Dorado
AIMS: Remote ischaemic conditioning (RIC) releases a humoural factor able to exert cross-species cardioprotection when plasma dialysate is applied to isolated hearts. However, the exact chemical nature of this factor is currently unknown. METHODS AND RESULTS: RIC (4 × 5min femoral occlusion/5min reperfusion) was applied to 10 male pigs, and blood was taken before and after the manoeuvre. Discriminant analysis of (1)H-NMR spectra (n = 10-12) obtained from plasma dialysates (12-14 kDa cut-off) allowed to demonstrate a different metabolic profile between control and postRIC samples, with lactate (2...
January 2017: Cardiovascular Research
https://www.readbyqxmd.com/read/28059133/prediction-of-n-methyl-d-aspartate-receptor-glun1-ligand-binding-affinity-by-a-novel-svm-pose-svm-score-combinatorial-ensemble-docking-scheme
#7
Max K Leong, Ren-Guei Syu, Yi-Lung Ding, Ching-Feng Weng
The glycine-binding site of the N-methyl-D-aspartate receptor (NMDAR) subunit GluN1 is a potential pharmacological target for neurodegenerative disorders. A novel combinatorial ensemble docking scheme using ligand and protein conformation ensembles and customized support vector machine (SVM)-based models to select the docked pose and to predict the docking score was generated for predicting the NMDAR GluN1-ligand binding affinity. The predicted root mean square deviation (RMSD) values in pose by SVM-Pose models were found to be in good agreement with the observed values (n = 30, r(2) = 0...
January 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28050793/glycine-administration-alters-mapk-signaling-pathways-and-causes-neuronal-damage-in-rat-brain-putative-mechanisms-involved-in-the-neurological-dysfunction-in-nonketotic-hyperglycinemia
#8
Alana Pimentel Moura, Belisa Parmeggiani, Juciano Gasparotto, Mateus Grings, Gabriela Miranda Fernandez Cardoso, Bianca Seminotti, José Cláudio Fonseca Moreira, Daniel Pens Gelain, Moacir Wajner, Guilhian Leipnitz
High glycine (GLY) levels have been suggested to induce neurotoxic effects in the central nervous system of patients with nonketotic hyperglycinemia (NKH). Since the mechanisms involved in the neuropathophysiology of NKH are not totally established, we evaluated the effect of a single intracerebroventricular administration of GLY on the content of proteins involved in neuronal damage and inflammatory response, as well as on the phosphorylation of the MAPK p38, ERK1/2, and JNK in rat striatum and cerebral cortex...
January 3, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28032990/iterative-focused-screening-with-biological-fingerprints-identifies-selective-asc-1-inhibitors-distinct-from-traditional-high-throughput-screening
#9
Peter S Kutchukian, Lee Warren, Brian C Magliaro, Adam Amoss, Jason A Cassaday, Gregory O'Donnell, Brian Squadroni, Paul Zuck, Danette Pascarella, J Chris Culberson, Andrew J Cooke, Danielle Hurzy, Kelly-Ann Sondra Schlegel, Fiona Thomson, Eric N Johnson, Victor N Uebele, Jeffrey D Hermes, Sophie Parmentier-Batteur, Michael Finley
N-methyl-d-aspartate receptors (NMDARs) mediate glutamatergic signaling that is critical to cognitive processes in the central nervous system, and NMDAR hypofunction is thought to contribute to cognitive impairment observed in both schizophrenia and Alzheimer's disease. One approach to enhance the function of NMDAR is to increase the concentration of an NMDAR coagonist, such as glycine or d-serine, in the synaptic cleft. Inhibition of alanine-serine-cysteine transporter-1 (Asc-1), the primary transporter of d-serine, is attractive because the transporter is localized to neurons in brain regions critical to cognitive function, including the hippocampus and cortical layers III and IV, and is colocalized with d-serine and NMDARs...
January 6, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28032116/synaptic-inhibition-in-avian-interaural-level-difference-sound-localizing-neurons
#10
Rebecca J Curry, Yong Lu
Synaptic inhibition plays a fundamental role in the neural computation of the interaural level difference (ILD), an important cue for the localization of high-frequency sound. Here, we studied the inhibitory synaptic currents in the chicken posterior portion of the dorsal nucleus of the lateral lemniscus (LLDp), the first binaural level difference encoder of the avian auditory pathway. Using whole-cell recordings in brain slices, we provide the first evidence confirming a monosynaptic inhibition driven by direct electrical and chemical stimulation of the contralateral LLDp, establishing the reciprocal inhibitory connection between the two LLDps, a long-standing assumption in the field...
November 2016: ENeuro
https://www.readbyqxmd.com/read/28029385/a-conserved-gating-element-in-trpv6-channels
#11
REVIEW
Laura Hofmann, Hongmei Wang, Andreas Beck, Ulrich Wissenbach, Veit Flockerzi
The Ca(2+)-selective tetrameric Transient Receptor Potential Vanilloid 6 (TRPV6) channel is an inwardly rectifying ion channel. The constitutive current endures Ca(2+)-induced inactivation as a result of the activation of phospholipase C followed depletion of phosphatidylinositol 4,5-bisphosphate, and calmodulin binding. Replacing a glycine residue within the cytosolic S4-S5 linker of the human TRPV6 protein, glycine 516, which is conserved in all TRP channel proteins, by a serine residue forces the channels into an open conformation thereby enhancing constitutive Ca(2+) entry and preventing inactivation...
October 28, 2016: Cell Calcium
https://www.readbyqxmd.com/read/28026001/expression-of-glycine-receptors-and-gephyrin-in-rat-medial-vestibular-nuclei-and-flocculi-following-unilateral-labyrinthectomy
#12
Wen Zhou, Liu-Qing Zhou, Hong Shi, Yang-Ming Leng, Bo Liu, Su-Lin Zhang, Wei-Jia Kong
The medial vestibular nucleus (MVN) and the cerebellar flocculus have been known to be the key areas involved in vestibular compensation (VC) following unilateral labyrinthectomy (UL). In this study, we examined the role of gephyrin and glycine receptor (GlyR) in VC using Sprague-Dawley rats, in an aim to gain deeper insight into the mechanisms responsible for VC. The expression of the α1 and β subunits of GlyR and gephyrin was immunohistochemically localized in rat MVN and flocculi. The mRNA and protein expression of GlyR (α1 and β subunits) and gephyrin was quantitatively determined by RT-qPCR and western blot analysis at 8 h, and at 1, 3 and 7 days following UL...
November 2016: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28018382/identification-and-analysis-of-nahco3-stress-responsive-genes-in-wild-soybean-glycine-soja-roots-by-rna-seq
#13
Jinlong Zhang, Jiaxue Wang, Wei Jiang, Juge Liu, Songnan Yang, Junyi Gai, Yan Li
Soil alkalinity is a major abiotic constraint to crop productivity and quality. Wild soybean (Glycine soja) is considered to be more stress-tolerant than cultivated soybean (G. max), and has considerable genetic variation for increasing alkalinity tolerance of soybean. In this study, we analyzed the transcriptome profile in the roots of an alkalinity tolerant wild soybean variety N24852 at 12 and 24 h after 90 mM NaHCO3 stress by RNA-sequencing. Compared with the controls, a total of 449 differentially expressed genes (DEGs) were identified, including 95 and 140 up-regulated genes, and 108 and 135 down-regulated genes at 12 and 24 h after NaHCO3 treatment, respectively...
2016: Frontiers in Plant Science
https://www.readbyqxmd.com/read/28010187/components-of-the-snare-containing-regulon-are-co-regulated-in-root-cells-undergoing-defense
#14
Vincent P Klink, Keshav Sharma, Shankar R Pant, Brant McNeece, Prakash Niraula, Gary W Lawrence
The term regulon has been coined in the genetic model plant Arabidopsis thaliana, denoting a structural and physiological defense apparatus defined genetically through the identification of the penetration (pen) mutants. The regulon is composed partially by the soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor (SNARE) syntaxin PEN1. PEN1 has homology to a Saccharomyces cerevisae gene that regulates a Secretion (Sec) protein, Suppressor of Sec 1 (Sso1p). The regulon is also composed of the β-glucosidase (PEN2) and an ATP binding cassette (ABC) transporter (PEN3)...
December 23, 2016: Plant Signaling & Behavior
https://www.readbyqxmd.com/read/28001399/the-discovery-and-hit-to-lead-optimization-of-tricyclic-sulfonamides-as-potent-and-efficacious-potentiators-of-glycine-receptors
#15
Howard Bregman, Jeffrey R Simard, Kristin L Andrews, Shawn Ayube, Hao Chen, Hakan Gunaydin, Angel Guzman-Perez, Jiali Hu, Liyue Huang, Xin Huang, Paul H Krolikowski, Sonya G Lehto, Richard T Lewis, Klaus Michelsen, Pamela Pegman, Matthew H Plant, Paul L Shaffer, Yohannes Teffera, Shuyan Yi, Maosheng Zhang, Jacinthe Gingras, Erin F DiMauro
Current pain therapeutics suffer from undesirable psychotropic and sedative side effects, as well as abuse potential. Glycine receptors (GlyRs) are inhibitory ligand-gated ion channels expressed in nerves of the spinal dorsal horn, where their activation is believed to reduce transmission of painful stimuli. Herein, we describe the identification and hit-to-lead optimization of a novel class of tricyclic sulfonamides as allosteric GlyR potentiators. Initial optimization of high-throughput screening (HTS) hit 1 led to the identification of 3, which demonstrated ex vivo potentiation of glycine-activated current in mouse dorsal horn neurons from spinal cord slices...
December 21, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27993973/anaplasma-marginale-outer-membrane-protein-a-is-an-adhesin-that-recognizes-sialylated-and-fucosylated-glycans-and-functionally-depends-on-an-essential-binding-domain
#16
Kathryn S Hebert, David Seidman, Aminat T Oki, Jerilyn Izac, Sarvani Emani, Lee D Oliver, Daniel P Miller, Brittney K Tegels, Reiji Kannagi, Richard T Marconi, Jason A Carlyon
Anaplasma marginale causes bovine anaplasmosis, a debilitating and potentially fatal tick-borne infection of cattle. Because A. marginale is an obligate intracellular organism, its adhesins that mediate entry into host cells are essential for survival. Here, we demonstrate that A. marginale outer membrane protein A (AmOmpA; AM854) contributes to the invasion of mammalian and tick host cells. AmOmpA exhibits predicted structural homology to OmpA of A. phagocytophilum (ApOmpA), an adhesin that uses key lysine and glycine residues to interact with α2,3-sialylated and α1,3-fucosylated glycan receptors, including 6-sulfo-sialyl Lewis x...
December 19, 2016: Infection and Immunity
https://www.readbyqxmd.com/read/27993721/foot-and-mouth-disease-virus-like-particles-as-integrin-based-drug-delivery-system-achieve-targeting-anti-tumor-efficacy
#17
Dan Yan, Zhidong Teng, Shiqi Sun, Shan Jiang, Hu Dong, Yuan Gao, Yanquan Wei, Wenwu Qin, Xiangtao Liu, Hong Yin, Huichen Guo
The surface of foot-and-mouth disease virus (FMDV)-like particles (VLPs) contains a conserved arginine-glycine-aspartic acid (RGD) motif. Natural FMDV specifically attaches to overexpressed integrin receptors in several cancer cells. The FMDV VLPs produced in Escherichia coli were used for the first time as a delivery system of anti-tumor drug doxorubicin (DOX). The DOX-loaded VLPs exhibited a distinct release profile in different physiological conditions. The effects of FMDV-VLPs-DOX on cellular internalization and viability were evaluated in vitro by cell imaging, MTT assay and apoptosis, respectively...
December 18, 2016: Nanomedicine: Nanotechnology, Biology, and Medicine
https://www.readbyqxmd.com/read/27991902/crystal-structures-of-human-glycine-receptor-%C3%AE-3-bound-to-a-novel-class-of-analgesic-potentiators
#18
Xin Huang, Paul L Shaffer, Shawn Ayube, Howard Bregman, Hao Chen, Sonya G Lehto, Jason A Luther, David J Matson, Stefan I McDonough, Klaus Michelsen, Matthew H Plant, Stephen Schneider, Jeffrey R Simard, Yohannes Teffera, Shuyan Yi, Maosheng Zhang, Erin F DiMauro, Jacinthe Gingras
Current therapies to treat persistent pain and neuropathic pain are limited by poor efficacy, side effects and risk of addiction. Here, we present a novel class of potent selective, central nervous system (CNS)-penetrant potentiators of glycine receptors (GlyRs), ligand-gated ion channels expressed in the CNS. AM-1488 increased the response to exogenous glycine in mouse spinal cord and significantly reversed mechanical allodynia induced by nerve injury in a mouse model of neuropathic pain. We obtained an X-ray crystal structure of human homopentameric GlyRα3 in complex with AM-3607, a potentiator of the same class with increased potency, and the agonist glycine, at 2...
December 19, 2016: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/27988386/new-approaches-to-target-glycinergic-neurotransmission-for-the-treatment-of-chronic-pain
#19
Wendy L Imlach
Inhibitory glycinergic neurotransmission in the spinal cord dorsal horn plays an important role in regulating nociceptive signalling by inhibiting neuronal excitation. Blocking glycinergic transmission in the dorsal horn causes normally innocuous stimuli to become painful (allodynia) and increases sensitivity to noxious stimuli (hyperalgesia). Loss of inhibitory signalling is thought to contribute to the development of pathological pain. Management of neuropathic pain with current therapeutics is challenging and there is a great need for more effective treatments...
December 14, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/27984198/effects-of-pregabalin-on-spinal-d-serine-content-and-nmda-receptor-mediated-synaptic-transmission-in-mice-with-neuropathic-pain
#20
Eiko Kato, Rie Matsuzawa, Shunsaku Kobayashi, Teruyuki Fukushima, Masao Maekawa, Yuuichi Hori
Pregabalin (PGB) is a chemical derivative of the inhibitory neurotransmitter γ-aminobutyric acid, and is successfully used for the treatment of neuropathic pain. Substantial evidence suggests that D-serine, an endogenous co-agonist at the strychnine-insensitive glycine site of the NMDA receptor, counteracts the antinociceptive actions of PGB at the level of the spinal cord. In the present study, we examined the impact of PGB treatment on spinal D-serine content and NMDA receptor-mediated synaptic transmission in the superficial dorsal horn of peripheral nerve-ligated neuropathic mice...
October 28, 2016: Neuroscience Letters
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