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Chr21 Protein-Protein Interactions: Enrichment in Products Involved in Intellectual Disabilities, Autism and Late Onset Alzheimer Disease
bioRxiv preprint doi: https://doi.org/10.1101/2019.12.11.872606; this version posted December 12, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Chr21 protein-protein interactions: enrichment in products involved in intellectual disabilities, autism and Late Onset Alzheimer Disease Julia Viard1,2*, Yann Loe-Mie1*, Rachel Daudin1, Malik Khelfaoui1, Christine Plancon2, Anne Boland2, Francisco Tejedor3, Richard L. Huganir4, Eunjoon Kim5, Makoto Kinoshita6, Guofa Liu7, Volker Haucke8, Thomas Moncion9, Eugene Yu10, Valérie Hindie9, Henri Bléhaut11, Clotilde Mircher12, Yann Herault13,14,15,16,17, Jean-François Deleuze2, Jean- Christophe Rain9, Michel Simonneau1, 18, 19, 20** and Aude-Marie Lepagnol- Bestel1** 1 Centre Psychiatrie & Neurosciences, INSERM U894, 75014 Paris, France 2 Laboratoire de génomique fonctionnelle, CNG, CEA, Evry 3 Instituto de Neurociencias CSIC-UMH, Universidad Miguel Hernandez-Campus de San Juan 03550 San Juan (Alicante), Spain 4 Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205 USA 5 Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon 34141, Republic of Korea 6 Department of Molecular Biology, Division of Biological Science, Nagoya University Graduate School of Science, Furo, Chikusa, Nagoya, Japan 7 Department of Biological Sciences, University of Toledo, Toledo, OH, 43606, USA 8 Leibniz Forschungsinstitut für Molekulare Pharmakologie -
Multiple Interactions Between an Arf/GEF Complex and Charged Lipids Determine Activation Kinetics on the Membrane
Multiple interactions between an Arf/GEF complex and charged lipids determine activation kinetics on the membrane Deepti Karandura,b,1, Agata Nawrotekc,d,1, John Kuriyana,b,2, and Jacqueline Cherfilsc,d,2 aDepartment of Molecular and Cell Biology, University of California, Berkeley, CA 94720; bHoward Hughes Medical Institute, University of California, Berkeley, CA 94720; cLaboratoire de Biologie et Pharmacologie Appliquée, CNRS, Cachan 94235, France; and dEcole Normale Supérieure Paris-Saclay, Cachan 94235, France Edited by Satyajit Mayor, National Centre for Biological Sciences, Bangalore, India, and approved August 28, 2017 (received for review May 15, 2017) Lipidated small GTPases and their regulators need to bind to which is surrounded by an assortment of regulatory domains (9). membranes to propagate actions in the cell, but an integrated Sec7-assisted nucleotide exchangeoccursinastep-by-step manner, understanding of how the lipid bilayer exerts its effect has whereby the Sec7 domain binds to the switch 1 and switch 2 regions remained elusive. Here we focused on ADP ribosylation factor of Arf to remodel the interswitch and inserts an invariant gluta- (Arf) GTPases, which orchestrate a variety of regulatory functions mate into the nucleotide-binding site to displace GDP (6, 7, 10). in lipid and membrane trafficking, and their activation by the In metazoans, Arf GTPases are activated at the plasma mem- guanine-nucleotide exchange factor (GEF) Brag2, which controls brane and on endosomes by members of three ArfGEF subfamilies: integrin endocytosis and cell adhesion and is impaired in cancer cytohesins, EFA6, and Brag/IQSEC. These ArfGEFs share a com- and developmental diseases. Biochemical and structural data are mon organization in which the Sec7 domain is immediately followed available that showed the exceptional efficiency of Arf activation by a pleckstrin homology (PH) domain that binds phosphoinositide by Brag2 on membranes. -
The Mineralocorticoid Receptor Leads to Increased Expression of EGFR
www.nature.com/scientificreports OPEN The mineralocorticoid receptor leads to increased expression of EGFR and T‑type calcium channels that support HL‑1 cell hypertrophy Katharina Stroedecke1,2, Sandra Meinel1,2, Fritz Markwardt1, Udo Kloeckner1, Nicole Straetz1, Katja Quarch1, Barbara Schreier1, Michael Kopf1, Michael Gekle1 & Claudia Grossmann1* The EGF receptor (EGFR) has been extensively studied in tumor biology and recently a role in cardiovascular pathophysiology was suggested. The mineralocorticoid receptor (MR) is an important efector of the renin–angiotensin–aldosterone‑system and elicits pathophysiological efects in the cardiovascular system; however, the underlying molecular mechanisms are unclear. Our aim was to investigate the importance of EGFR for MR‑mediated cardiovascular pathophysiology because MR is known to induce EGFR expression. We identifed a SNP within the EGFR promoter that modulates MR‑induced EGFR expression. In RNA‑sequencing and qPCR experiments in heart tissue of EGFR KO and WT mice, changes in EGFR abundance led to diferential expression of cardiac ion channels, especially of the T‑type calcium channel CACNA1H. Accordingly, CACNA1H expression was increased in WT mice after in vivo MR activation by aldosterone but not in respective EGFR KO mice. Aldosterone‑ and EGF‑responsiveness of CACNA1H expression was confrmed in HL‑1 cells by Western blot and by measuring peak current density of T‑type calcium channels. Aldosterone‑induced CACNA1H protein expression could be abrogated by the EGFR inhibitor AG1478. Furthermore, inhibition of T‑type calcium channels with mibefradil or ML218 reduced diameter, volume and BNP levels in HL‑1 cells. In conclusion the MR regulates EGFR and CACNA1H expression, which has an efect on HL‑1 cell diameter, and the extent of this regulation seems to depend on the SNP‑216 (G/T) genotype. -
Aquaporin Channels in the Heart—Physiology and Pathophysiology
International Journal of Molecular Sciences Review Aquaporin Channels in the Heart—Physiology and Pathophysiology Arie O. Verkerk 1,2,* , Elisabeth M. Lodder 2 and Ronald Wilders 1 1 Department of Medical Biology, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; [email protected] 2 Department of Experimental Cardiology, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; [email protected] * Correspondence: [email protected]; Tel.: +31-20-5664670 Received: 29 March 2019; Accepted: 23 April 2019; Published: 25 April 2019 Abstract: Mammalian aquaporins (AQPs) are transmembrane channels expressed in a large variety of cells and tissues throughout the body. They are known as water channels, but they also facilitate the transport of small solutes, gasses, and monovalent cations. To date, 13 different AQPs, encoded by the genes AQP0–AQP12, have been identified in mammals, which regulate various important biological functions in kidney, brain, lung, digestive system, eye, and skin. Consequently, dysfunction of AQPs is involved in a wide variety of disorders. AQPs are also present in the heart, even with a specific distribution pattern in cardiomyocytes, but whether their presence is essential for proper (electro)physiological cardiac function has not intensively been studied. This review summarizes recent findings and highlights the involvement of AQPs in normal and pathological cardiac function. We conclude that AQPs are at least implicated in proper cardiac water homeostasis and energy balance as well as heart failure and arsenic cardiotoxicity. However, this review also demonstrates that many effects of cardiac AQPs, especially on excitation-contraction coupling processes, are virtually unexplored. -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
The Metabotropic Glutamate Receptor Mglur1 Regulates the Voltage-Gated Potassium Channel Kv1.2 Through Agonist-Dependent and Agonist-Independent Mechanisms
University of Vermont ScholarWorks @ UVM Graduate College Dissertations and Theses Dissertations and Theses 2019 The etM abotropic glutamate receptor mGluR1 regulates the voltage-gated potassium channel Kv1.2 through agonist-dependent and agonist- independent mechanisms Sharath Chandra Madasu University of Vermont Follow this and additional works at: https://scholarworks.uvm.edu/graddis Part of the Cell Biology Commons, Neuroscience and Neurobiology Commons, and the Pharmacology Commons Recommended Citation Madasu, Sharath Chandra, "The eM tabotropic glutamate receptor mGluR1 regulates the voltage-gated potassium channel Kv1.2 through agonist-dependent and agonist-independent mechanisms" (2019). Graduate College Dissertations and Theses. 982. https://scholarworks.uvm.edu/graddis/982 This Dissertation is brought to you for free and open access by the Dissertations and Theses at ScholarWorks @ UVM. It has been accepted for inclusion in Graduate College Dissertations and Theses by an authorized administrator of ScholarWorks @ UVM. For more information, please contact [email protected]. THE METABOTROPIC GLUTAMATE RECEPTOR MGLUR1 REGULATES THE VOLTAGE-GATED POTASSIUM CHANNEL KV1.2 THROUGH AGONIST-DEPENDENT AND AGONIST-INDEPENDENT MECHANISMS. A Dissertation Presented by Sharath Chandra Madasu to The Faculty of the Graduate College of The University of Vermont In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Specializing in Cellular Molecular and Biomedical Science January, 2019 Defense Date: September 27, 2018 Dissertation Examination Committee: Anthony D. Morielli, PhD., Advisor John Green, PhD., Chairperson Karen Lounsbury, Ph.D. Benedek Erdos, PhD. Cynthia J. Forehand, Ph.D., Dean of the Graduate College ABSTRACT The voltage gated potassium channel Kv1.2 plays a key role in the central nervous system and mutations in Kv1.2 cause neurological disorders such as epilepsies and ataxias. -
Transcriptomic Analysis of Native Versus Cultured Human and Mouse Dorsal Root Ganglia Focused on Pharmacological Targets Short
bioRxiv preprint doi: https://doi.org/10.1101/766865; this version posted September 12, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. Transcriptomic analysis of native versus cultured human and mouse dorsal root ganglia focused on pharmacological targets Short title: Comparative transcriptomics of acutely dissected versus cultured DRGs Andi Wangzhou1, Lisa A. McIlvried2, Candler Paige1, Paulino Barragan-Iglesias1, Carolyn A. Guzman1, Gregory Dussor1, Pradipta R. Ray1,#, Robert W. Gereau IV2, # and Theodore J. Price1, # 1The University of Texas at Dallas, School of Behavioral and Brain Sciences and Center for Advanced Pain Studies, 800 W Campbell Rd. Richardson, TX, 75080, USA 2Washington University Pain Center and Department of Anesthesiology, Washington University School of Medicine # corresponding authors [email protected], [email protected] and [email protected] Funding: NIH grants T32DA007261 (LM); NS065926 and NS102161 (TJP); NS106953 and NS042595 (RWG). The authors declare no conflicts of interest Author Contributions Conceived of the Project: PRR, RWG IV and TJP Performed Experiments: AW, LAM, CP, PB-I Supervised Experiments: GD, RWG IV, TJP Analyzed Data: AW, LAM, CP, CAG, PRR Supervised Bioinformatics Analysis: PRR Drew Figures: AW, PRR Wrote and Edited Manuscript: AW, LAM, CP, GD, PRR, RWG IV, TJP All authors approved the final version of the manuscript. 1 bioRxiv preprint doi: https://doi.org/10.1101/766865; this version posted September 12, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. -
Incorrect Dosage of IQSEC2, a Known Intellectual Disability and Epilepsy Gene, Disrupts Dendritic Spine Morphogenesis
OPEN Citation: Transl Psychiatry (2017) 7, e1110; doi:10.1038/tp.2017.81 www.nature.com/tp ORIGINAL ARTICLE Incorrect dosage of IQSEC2, a known intellectual disability and epilepsy gene, disrupts dendritic spine morphogenesis SJ Hinze1,2, MR Jackson1,2, S Lie1, L Jolly1,2, M Field3, SC Barry2, RJ Harvey4 and C Shoubridge1,2 There is considerable genetic and phenotypic heterogeneity associated with intellectual disability (ID), specific learning disabilities, attention-deficit hyperactivity disorder, autism and epilepsy. The intelligence quotient (IQ) motif and SEC7 domain containing protein 2 gene (IQSEC2) is located on the X-chromosome and harbors mutations that contribute to non-syndromic ID with and without early-onset seizure phenotypes in both sexes. Although IQ and Sec7 domain mutations lead to partial loss of IQSEC2 enzymatic activity, the in vivo pathogenesis resulting from these mutations is not known. Here we reveal that IQSEC2 has a key role in dendritic spine morphology. Partial loss-of-function mutations were modeled using a lentiviral short hairpin RNA (shRNA) approach, which achieved a 57% knockdown of Iqsec2 expression in primary hippocampal cell cultures from mice. Investigating gross morphological parameters after 8 days of in vitro culture (8DIV) identified a 32% reduction in primary axon length, in contrast to a 27% and 31% increase in the number and complexity of dendrites protruding from the cell body, respectively. This increase in dendritic complexity and spread was carried through dendritic spine development, with a 34% increase in the number of protrusions per dendritic segment compared with controls at 15DIV. Although the number of dendritic spines had normalized by 21DIV, a reduction was noted in the number of immature spines. -
Supplemental Table 1. Complete Gene Lists and GO Terms from Figure 3C
Supplemental Table 1. Complete gene lists and GO terms from Figure 3C. Path 1 Genes: RP11-34P13.15, RP4-758J18.10, VWA1, CHD5, AZIN2, FOXO6, RP11-403I13.8, ARHGAP30, RGS4, LRRN2, RASSF5, SERTAD4, GJC2, RHOU, REEP1, FOXI3, SH3RF3, COL4A4, ZDHHC23, FGFR3, PPP2R2C, CTD-2031P19.4, RNF182, GRM4, PRR15, DGKI, CHMP4C, CALB1, SPAG1, KLF4, ENG, RET, GDF10, ADAMTS14, SPOCK2, MBL1P, ADAM8, LRP4-AS1, CARNS1, DGAT2, CRYAB, AP000783.1, OPCML, PLEKHG6, GDF3, EMP1, RASSF9, FAM101A, STON2, GREM1, ACTC1, CORO2B, FURIN, WFIKKN1, BAIAP3, TMC5, HS3ST4, ZFHX3, NLRP1, RASD1, CACNG4, EMILIN2, L3MBTL4, KLHL14, HMSD, RP11-849I19.1, SALL3, GADD45B, KANK3, CTC- 526N19.1, ZNF888, MMP9, BMP7, PIK3IP1, MCHR1, SYTL5, CAMK2N1, PINK1, ID3, PTPRU, MANEAL, MCOLN3, LRRC8C, NTNG1, KCNC4, RP11, 430C7.5, C1orf95, ID2-AS1, ID2, GDF7, KCNG3, RGPD8, PSD4, CCDC74B, BMPR2, KAT2B, LINC00693, ZNF654, FILIP1L, SH3TC1, CPEB2, NPFFR2, TRPC3, RP11-752L20.3, FAM198B, TLL1, CDH9, PDZD2, CHSY3, GALNT10, FOXQ1, ATXN1, ID4, COL11A2, CNR1, GTF2IP4, FZD1, PAX5, RP11-35N6.1, UNC5B, NKX1-2, FAM196A, EBF3, PRRG4, LRP4, SYT7, PLBD1, GRASP, ALX1, HIP1R, LPAR6, SLITRK6, C16orf89, RP11-491F9.1, MMP2, B3GNT9, NXPH3, TNRC6C-AS1, LDLRAD4, NOL4, SMAD7, HCN2, PDE4A, KANK2, SAMD1, EXOC3L2, IL11, EMILIN3, KCNB1, DOK5, EEF1A2, A4GALT, ADGRG2, ELF4, ABCD1 Term Count % PValue Genes regulation of pathway-restricted GDF3, SMAD7, GDF7, BMPR2, GDF10, GREM1, BMP7, LDLRAD4, SMAD protein phosphorylation 9 6.34 1.31E-08 ENG pathway-restricted SMAD protein GDF3, SMAD7, GDF7, BMPR2, GDF10, GREM1, BMP7, LDLRAD4, phosphorylation -
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. -
Characterizing the Mechanisms of Kappa Opioid Receptor Signaling Within Mesolimbic Dopamine Circuitry Katie Reichard a Dissertat
Characterizing the mechanisms of kappa opioid receptor signaling within mesolimbic dopamine circuitry Katie Reichard A dissertation submitted in partial fulfillment of the degree requirements for the degree of: Doctor of Philosophy University of Washington 2020 Reading Committee: Charles Chavkin, Chair Paul Phillips Larry Zweifel Program Authorized to Confer Degree: Neuroscience Graduate Program TABLE OF CONTENTS Summary/Abstract………………………………………………………………………….……..6 Dedication……………………………………………………………………………….………...9 Chapter 1 The therapeutic potential of the targeting the kappa opioid receptor system in stress- associated mental health disorders……………………………….………………………………10 Section 1.1 Activation of the dynorphin/kappa opioid receptor system is associated with dysphoria, cognitive disruption, and increased preference for drugs of abuse…………………..13 Section 1.2 Contribution of the dyn/KOR system to substance use disorder, anxiety, and depression………………………………………………………………………………………..15 Section 1.3 KORs are expressed on dorsal raphe serotonin neurons and contribute to stress- induced plasticity with serotonin circuitry……………………………………………………….17 Section 1.4 Kappa opioid receptor expression in the VTA contributes to the behavioral response to stress……………………………………………………………………………………....…..19 Section 1.5 Other brain regions contributing to the KOR-mediated response to stress…………23 Section 1.6 G Protein signaling at the KOR …………………………………………………….25 Chapter 2: JNK-Receptor Inactivation Affects D2 Receptor through both agonist action and norBNI-mediated cross-inactivation -
Cross-Subunit Interactions That Stabilize Open States Mediate Gating in NMDA Receptors
Cross-subunit interactions that stabilize open states mediate gating in NMDA receptors Gary J. Iacobuccia,1, Han Wenb,1, Matthew Heloua, Beiying Liua, Wenjun Zhengb,2,3, and Gabriela K. Popescua,2,3 aDepartment of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, SUNY, Buffalo, NY 14203; and bDepartment of Physics, College of Arts and Sciences, University at Buffalo, SUNY, Buffalo, NY 14260 Edited by Richard W. Aldrich, The University of Texas at Austin, Austin, TX, and approved December 1, 2020 (received for review April 19, 2020) NMDA receptors are excitatory channels with critical functions in helices (M1, M3, and M4) and an internally facing P-loop (M2). the physiology of central synapses. Their activation reaction The external portion of each subunit consists of two stacked proceeds as a series of kinetically distinguishable, reversible steps, globular domains, the N-terminal (NTD) and ligand-binding whose structural bases are currently under investigation. Very (LBD) domains, for which several atomic-resolution structures ex- likely, the earliest steps include glutamate binding to glycine-bound ist (10, 11). In contrast, the cytoplasmic C-terminal domain (CTD), receptors and subsequent constriction of the ligand-binding do- which is least conserved across subunits, appears largely disor- main. Later, three short linkers transduce this movement to open dered. Although critically important for the receptor’s cellular the gate by mechanical pulling on transmembrane helices. Here, functions, the