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International Journal of Molecular Sciences Article Phenotypic Subtyping and Re-Analysis of Existing Methylation Data from Autistic Probands in Simplex Families Reveal ASD Subtype-Associated Differentially Methylated Genes and Biological Functions Elizabeth C. Lee y and Valerie W. Hu * Department of Biochemistry and Molecular Medicine, The George Washington University, School of Medicine and Health Sciences, Washington, DC 20037, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-202-994-8431 Current address: W. Harry Feinstone Department of Molecular Microbiology and Immunology, y Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA. Received: 25 August 2020; Accepted: 17 September 2020; Published: 19 September 2020 Abstract: Autism spectrum disorder (ASD) describes a group of neurodevelopmental disorders with core deficits in social communication and manifestation of restricted, repetitive, and stereotyped behaviors. Despite the core symptomatology, ASD is extremely heterogeneous with respect to the severity of symptoms and behaviors. This heterogeneity presents an inherent challenge to all large-scale genome-wide omics analyses. In the present study, we address this heterogeneity by stratifying ASD probands from simplex families according to the severity of behavioral scores on the Autism Diagnostic Interview-Revised diagnostic instrument, followed by re-analysis of existing DNA methylation data from individuals in three ASD subphenotypes in comparison to that of their respective unaffected siblings. We demonstrate that subphenotyping of cases enables the identification of over 1.6 times the number of statistically significant differentially methylated regions (DMR) and DMR-associated genes (DAGs) between cases and controls, compared to that identified when all cases are combined. Our analyses also reveal ASD-related neurological functions and comorbidities that are enriched among DAGs in each phenotypic subgroup but not in the combined case group. -
Characterization of Zebrafish GABAA Receptor Subunits
www.nature.com/scientificreports OPEN Characterization of zebrafsh GABAA receptor subunits Kenichiro Sadamitsu, Leona Shigemitsu, Marina Suzuki, Daishi Ito, Makoto Kashima & Hiromi Hirata* γ-Aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system, exerts its efect through the activation of GABA receptors. GABAA receptors are ligand-gated chloride channels composed of fve subunit proteins. Mammals have 19 diferent GABAA receptor subunits (α1–6, β1–3, γ1–3, δ, ε, π, θ, and ρ1–3), the physiological properties of which have been assayed by electrophysiology. However, the evolutionary conservation of the physiological characteristics of diverged GABAA receptor subunits remains unclear. Zebrafsh have 23 subunits (α1, α2a, α2b, α3–5, α6a, α6b, β1–4, γ1–3, δ, π, ζ, ρ1, ρ2a, ρ2b, ρ3a, and ρ3b), but the electrophysiological properties of these subunits have not been explored. In this study, we cloned the coding sequences for zebrafsh GABAA receptor subunits and investigated their expression patterns in larval zebrafsh by whole- mount in situ hybridization. We also performed electrophysiological recordings of GABA-evoked currents from Xenopus oocytes injected with one or multiple zebrafsh GABAA receptor subunit cRNAs and calculated the half-maximal efective concentrations (EC50s) for each. Our results revealed the spatial expressions and electrophysiological GABA sensitivities of zebrafsh GABAA receptors, suggesting that the properties of GABAA receptor subunits are conserved among vertebrates. γ-Aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system of vertebrates, 1 controls the excitability of neural networks mainly through GABA A receptors . Te GABAA receptor mediates two types of inhibition, known as phasic and tonic inhibition2. -
Sex Differences in Glutamate Receptor Gene Expression in Major Depression and Suicide
Molecular Psychiatry (2015) 20, 1057–1068 © 2015 Macmillan Publishers Limited All rights reserved 1359-4184/15 www.nature.com/mp IMMEDIATE COMMUNICATION Sex differences in glutamate receptor gene expression in major depression and suicide AL Gray1, TM Hyde2,3, A Deep-Soboslay2, JE Kleinman2 and MS Sodhi1,4 Accumulating data indicate that the glutamate system is disrupted in major depressive disorder (MDD), and recent clinical research suggests that ketamine, an antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor (GluR), has rapid antidepressant efficacy. Here we report findings from gene expression studies of a large cohort of postmortem subjects, including subjects with MDD and controls. Our data reveal higher expression levels of the majority of glutamatergic genes tested in the dorsolateral prefrontal cortex (DLPFC) in MDD (F21,59 = 2.32, P = 0.006). Posthoc data indicate that these gene expression differences occurred mostly in the female subjects. Higher expression levels of GRIN1, GRIN2A-D, GRIA2-4, GRIK1-2, GRM1, GRM4, GRM5 and GRM7 were detected in the female patients with MDD. In contrast, GRM5 expression was lower in male MDD patients relative to male controls. When MDD suicides were compared with MDD non-suicides, GRIN2B, GRIK3 and GRM2 were expressed at higher levels in the suicides. Higher expression levels were detected for several additional genes, but these were not statistically significant after correction for multiple comparisons. In summary, our analyses indicate a generalized disruption of the regulation of the GluRs in the DLPFC of females with MDD, with more specific GluR alterations in the suicides and in the male groups. -
Tumor Barrier in Brain Metastases
ARTICLE DOI: 10.1038/s41467-018-05030-w OPEN Reactive astrocytic S1P3 signaling modulates the blood–tumor barrier in brain metastases Brunilde Gril 1, Anurag N. Paranjape 1, Stephan Woditschka1,17, Emily Hua1, Emma L. Dolan1, Jeffrey Hanson2, Xiaolin Wu3, Wojciech Kloc4,5, Ewa Izycka-Swieszewska 6,7, Renata Duchnowska 8, Rafał Pęksa 9, Wojciech Biernat9, Jacek Jassem10, Naema Nayyar11, Priscilla K. Brastianos11, O. Morgan Hall12, Cody J. Peer12, William D. Figg12, Gary T. Pauly 13, Christina Robinson14, Simone Difilippantonio14, Emilie Bialecki15, Philippe Metellus15,16, Joel P. Schneider13 & Patricia S. Steeg1 1234567890():,; Brain metastases are devastating complications of cancer. The blood–brain barrier (BBB), which protects the normal brain, morphs into an inadequately characterized blood–tumor barrier (BTB) when brain metastases form, and is surrounded by a neuroinflammatory response. These structures contribute to poor therapeutic efficacy by limiting drug uptake. Here, we report that experimental breast cancer brain metastases of low- and high perme- ability to a dextran dye exhibit distinct microenvironmental gene expression patterns. Astrocytic sphingosine-1 phosphate receptor 3 (S1P3) is upregulated in the neuroin- flammatory response of the highly permeable lesions, and is expressed in patients’ brain metastases. S1P3 inhibition functionally tightens the BTB in vitro and in vivo. S1P3 mediates its effects on BTB permeability through astrocytic secretion of IL-6 and CCL2, which relaxes endothelial cell adhesion. Tumor cell overexpression of S1P3 mimics this pathway, enhancing IL-6 and CCL-2 production and elevating BTB permeability. In conclusion, neuroinflammatory astrocytic S1P3 modulates BTB permeability. 1 Women’s Malignancies Branch, CCR, NCI, Bethesda 20892 MD, USA. -
Differential Co-Assembly of Α1-Gabaars Associated with Epileptic Encephalopathy
Research Report: Regular Manuscript Differential co-assembly of α1-GABAARs associated with epileptic encephalopathy https://doi.org/10.1523/JNEUROSCI.2748-19.2020 Cite as: J. Neurosci 2020; 10.1523/JNEUROSCI.2748-19.2020 Received: 18 November 2019 Revised: 5 May 2020 Accepted: 6 May 2020 This Early Release article has been peer-reviewed and accepted, but has not been through the composition and copyediting processes. The final version may differ slightly in style or formatting and will contain links to any extended data. Alerts: Sign up at www.jneurosci.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Copyright © 2020 the authors 1 Differential co-assembly of α1-GABAARs 2 associated with epileptic encephalopathy 3 4 5 Saad Hannan1*, Aida H. B. Affandi1, Marielle Minere1¶, Charlotte Jones1, Pollyanna Goh2, 6 Gary Warnes2, Bernt Popp3,4, Regina Trollmann5, Dean Nizetic2,6 & Trevor G. Smart1* 7 8 1. Department of Neuroscience, Physiology and Pharmacology, University College London, 9 Gower Street, London WC1E 6BT, UK 10 2. The Blizard Institute, Barts & The London School of Medicine, Queen Mary University of 11 London, 4 Newark Street, London, E1 2AT, UK 12 3. Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-Universität 13 Erlangen-Nürnberg (FAU), Schwabachanlage 10, 91054 Erlangen, Germany. 14 4. Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, 15 Germany. 16 5. Department of Pediatrics, Division of Neuropediatrics, -
Gabaergic Signaling Linked to Autophagy Enhances Host Protection Against Intracellular Bacterial Infections
ARTICLE DOI: 10.1038/s41467-018-06487-5 OPEN GABAergic signaling linked to autophagy enhances host protection against intracellular bacterial infections Jin Kyung Kim1,2,3, Yi Sak Kim1,2,3, Hye-Mi Lee1,3, Hyo Sun Jin4, Chiranjivi Neupane 2,5, Sup Kim1,2,3, Sang-Hee Lee6, Jung-Joon Min7, Miwa Sasai8, Jae-Ho Jeong 9,10, Seong-Kyu Choe11, Jin-Man Kim12, Masahiro Yamamoto8, Hyon E. Choy 9,10, Jin Bong Park 2,5 & Eun-Kyeong Jo1,2,3 1234567890():,; Gamma-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the brain; however, the roles of GABA in antimicrobial host defenses are largely unknown. Here we demonstrate that GABAergic activation enhances antimicrobial responses against intracel- lular bacterial infection. Intracellular bacterial infection decreases GABA levels in vitro in macrophages and in vivo in sera. Treatment of macrophages with GABA or GABAergic drugs promotes autophagy activation, enhances phagosomal maturation and antimicrobial responses against mycobacterial infection. In macrophages, the GABAergic defense is mediated via macrophage type A GABA receptor (GABAAR), intracellular calcium release, and the GABA type A receptor-associated protein-like 1 (GABARAPL1; an Atg8 homolog). Finally, GABAergic inhibition increases bacterial loads in mice and zebrafish in vivo, sug- gesting that the GABAergic defense plays an essential function in metazoan host defenses. Our study identified a previously unappreciated role for GABAergic signaling in linking antibacterial autophagy to enhance host innate defense against intracellular bacterial infection. 1 Department of Microbiology, Chungnam National University School of Medicine, Daejeon 35015, Korea. 2 Department of Medical Science, Chungnam National University School of Medicine, Daejeon 35015, Korea. -
Research Article Microarray-Based Comparisons of Ion Channel Expression Patterns: Human Keratinocytes to Reprogrammed Hipscs To
Hindawi Publishing Corporation Stem Cells International Volume 2013, Article ID 784629, 25 pages http://dx.doi.org/10.1155/2013/784629 Research Article Microarray-Based Comparisons of Ion Channel Expression Patterns: Human Keratinocytes to Reprogrammed hiPSCs to Differentiated Neuronal and Cardiac Progeny Leonhard Linta,1 Marianne Stockmann,1 Qiong Lin,2 André Lechel,3 Christian Proepper,1 Tobias M. Boeckers,1 Alexander Kleger,3 and Stefan Liebau1 1 InstituteforAnatomyCellBiology,UlmUniversity,Albert-EinsteinAllee11,89081Ulm,Germany 2 Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen, Pauwelstrasse 30, 52074 Aachen, Germany 3 Department of Internal Medicine I, Ulm University, Albert-Einstein Allee 11, 89081 Ulm, Germany Correspondence should be addressed to Alexander Kleger; [email protected] and Stefan Liebau; [email protected] Received 31 January 2013; Accepted 6 March 2013 Academic Editor: Michael Levin Copyright © 2013 Leonhard Linta et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Ion channels are involved in a large variety of cellular processes including stem cell differentiation. Numerous families of ion channels are present in the organism which can be distinguished by means of, for example, ion selectivity, gating mechanism, composition, or cell biological function. To characterize the distinct expression of this group of ion channels we have compared the mRNA expression levels of ion channel genes between human keratinocyte-derived induced pluripotent stem cells (hiPSCs) and their somatic cell source, keratinocytes from plucked human hair. This comparison revealed that 26% of the analyzed probes showed an upregulation of ion channels in hiPSCs while just 6% were downregulated. -
GRIN3A and MAPT Stimulate Nerve Overgrowth in Macrodactyly
MOLECULAR MEDICINE REPORTS 14: 5637-5643, 2016 GRIN3A and MAPT stimulate nerve overgrowth in macrodactyly XU SHI1*, LU LU2*, XIU JIN3, BIN LIU4, XIGUANG SUN4, LAIJIN LU4 and YANFANG JIANG1,5 1Department of Genetic Diagnosis Center, Central Laboratory; Departments of 2Breast Surgery, 3Burn Surgery and 4Hand and Foot Surgery, The First Hospital of Jilin University, Changchun, Jilin 130000; 5Key Laboratory of Zoonosis Research, Ministry of Education, Institute of Zoonosis, Jilin University, Changchun, Jilin 130000, P.R. China Received September 30, 2015; Accepted October 12, 2016 DOI: 10.3892/mmr.2016.5923 Abstract. As an uncommon and congenital condition, to abnormal nerve proliferation and underpin the pathogenesis macrodactyly is characterized by an increase in the size of all of macrodactyly, and provide potential application targets in the elements or structures of the digits or toes; however, the nerve tissue regeneration engineering. underlying pathogenesis remains to be fully elucidated. In the present study, the gene expression profiles of abnormal nerves Introduction were examined in three patients with macrodactyly using microarray analysis to identify potential genes contributing Macrodactyly is an uncommon congenital condition character- to nerve overgrowth. Gene expression profiling in the nerve ized by an increase in the size of all the elements or structures tissue samples were scanned using the microarray and the of the digits or toes, including phalanges, tendons, vessels, differentially expressed genes were verified at the transcrip- subcutaneous fat and finger nails. The malformation often tion level using reverse transcription-quantitative polymerase occurs unilaterally or asymmetrically and affects more than chain reaction analysis. Western blot analysis was used to one digit or toe. -
Stem Cells and Ion Channels
Stem Cells International Stem Cells and Ion Channels Guest Editors: Stefan Liebau, Alexander Kleger, Michael Levin, and Shan Ping Yu Stem Cells and Ion Channels Stem Cells International Stem Cells and Ion Channels Guest Editors: Stefan Liebau, Alexander Kleger, Michael Levin, and Shan Ping Yu Copyright © 2013 Hindawi Publishing Corporation. All rights reserved. This is a special issue published in “Stem Cells International.” All articles are open access articles distributed under the Creative Com- mons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Editorial Board Nadire N. Ali, UK Joseph Itskovitz-Eldor, Israel Pranela Rameshwar, USA Anthony Atala, USA Pavla Jendelova, Czech Republic Hannele T. Ruohola-Baker, USA Nissim Benvenisty, Israel Arne Jensen, Germany D. S. Sakaguchi, USA Kenneth Boheler, USA Sue Kimber, UK Paul R. Sanberg, USA Dominique Bonnet, UK Mark D. Kirk, USA Paul T. Sharpe, UK B. Bunnell, USA Gary E. Lyons, USA Ashok Shetty, USA Kevin D. Bunting, USA Athanasios Mantalaris, UK Igor Slukvin, USA Richard K. Burt, USA Pilar Martin-Duque, Spain Ann Steele, USA Gerald A. Colvin, USA EvaMezey,USA Alexander Storch, Germany Stephen Dalton, USA Karim Nayernia, UK Marc Turner, UK Leonard M. Eisenberg, USA K. Sue O’Shea, USA Su-Chun Zhang, USA Marina Emborg, USA J. Parent, USA Weian Zhao, USA Josef Fulka, Czech Republic Bruno Peault, USA Joel C. Glover, Norway Stefan Przyborski, UK Contents Stem Cells and Ion Channels, Stefan Liebau, -
Characterisation of GABAA Receptors and Cation-Chloride Cotransporters in the Uterus and Their Role in Pre-Term Labour
Characterisation of GABAA receptors and cation-chloride cotransporters in the uterus and their role in pre-term labour Melissa Linda Sutherland December 2017 Supervisors: Dr. Amy V. Poole, Dr. Jennifer A. Fraser, Dr. Claire Garden. A thesis submitted in partial fulfilment of the requirements of Edinburgh Napier University, for the award of Master by Research Declaration It is hereby declared that this thesis is the result of the author’s original research. It has been composed by the author and has not been previously submitted for examination, which has led to the award of a degree or professional qualification. Signed: Date: Contents page Abbreviations .............................................................................................. 1 Acknowledgements ................................................................................... 3 Abstract ......................................................................................................... 4 CHAPTER 1. Introduction ......................................................................... 5 1.1-aminobutyric acid (GABA) .............................................................. 5 1.2 GABA receptor structure and function .......................................... 5 Figure 1.1 Schematic diagram of the GABAA subunit and receptor ......................................................................................................... 6 1.3 GABAARs role in development central nervous system .......................................................................................................... -
Ion Channels
UC Davis UC Davis Previously Published Works Title THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Ion channels. Permalink https://escholarship.org/uc/item/1442g5hg Journal British journal of pharmacology, 176 Suppl 1(S1) ISSN 0007-1188 Authors Alexander, Stephen PH Mathie, Alistair Peters, John A et al. Publication Date 2019-12-01 DOI 10.1111/bph.14749 License https://creativecommons.org/licenses/by/4.0/ 4.0 Peer reviewed eScholarship.org Powered by the California Digital Library University of California S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2019/20: Ion channels. British Journal of Pharmacology (2019) 176, S142–S228 THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Ion channels Stephen PH Alexander1 , Alistair Mathie2 ,JohnAPeters3 , Emma L Veale2 , Jörg Striessnig4 , Eamonn Kelly5, Jane F Armstrong6 , Elena Faccenda6 ,SimonDHarding6 ,AdamJPawson6 , Joanna L Sharman6 , Christopher Southan6 , Jamie A Davies6 and CGTP Collaborators 1School of Life Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK 2Medway School of Pharmacy, The Universities of Greenwich and Kent at Medway, Anson Building, Central Avenue, Chatham Maritime, Chatham, Kent, ME4 4TB, UK 3Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK 4Pharmacology and Toxicology, Institute of Pharmacy, University of Innsbruck, A-6020 Innsbruck, Austria 5School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, UK 6Centre for Discovery Brain Science, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. -
Purinergic Receptor Transactivation by the Β2-Adrenergic Receptor Increases Intracellular Ca2+ in Non-Excitable Cells
Molecular Pharmacology Fast Forward. Published on March 9, 2017 as DOI: 10.1124/mol.116.106419 This article has not been copyedited and formatted. The final version may differ from this version. MOLPHARM/2016/106419 Title page: Purinergic receptor transactivation by the β2-adrenergic receptor increases intracellular Ca2+ in non-excitable cells. Wayne Stallaert, Emma T van der Westhuizen, Anne-Marie Schönegge, Bianca Plouffe, Mireille Downloaded from Hogue, Viktoria Lukashova, Asuka Inoue, Satoru Ishida, Junken Aoki, Christian Le Gouill & Michel Bouvier. molpharm.aspetjournals.org Department of Biochemistry, Université de Montréal, Montréal, QC, Canada (WS, ETvdW, A- MS, BP, MB). Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada (WS, ETvdW, A-MS, BP, MH, VL, CLG, MB). Monash Institute for at ASPET Journals on September 30, 2021 Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (ETvdW). Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan (AI, SI, JA). Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO), Kawaguchi, Saitama, Japan (AI). Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), Chiyoda-ku, Tokyo, Japan (JA). 1 Molecular Pharmacology Fast Forward. Published on March 9, 2017 as DOI: 10.1124/mol.116.106419 This article has not been copyedited and formatted. The final version may differ from this version. MOLPHARM/2016/106419 Running title page: a) Running title: β2AR transactivation of purinergic receptors b) Corresponding author: Michel Bouvier, IRIC - Université de Montréal, P.O. Box 6128 Succursale Centre-Ville, Montréal, Qc. Canada, H3C 3J7. Tel: +1-514-343-6319.