DOCSLIB.ORG

Crystallographic Insights Into Sodium-Channel Modulation by The

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Crystallographic Insights Into Sodium-Channel Modulation by The Crystallographic insights into sodium-channel PNAS PLUS modulation by the β4 subunit John Gilchrista,1, Samir Dasb,c,1, Filip Van Petegemb,c,2, and Frank Bosmansa,d,2 aDepartment of Physiology and dSolomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; and bDepartment of Biochemistry and Molecular Biology and the cLife Sciences Institute, University of British Columbia, Vancouver, V6T 1Z3 Canada Edited by Baldomero M. Olivera, University of Utah, Salt Lake City, UT, and approved November 4, 2013 (received for review July 31, 2013) Voltage-gated sodium (Nav) channels are embedded in a multicom- Moreover, the notion that the β4 subunit shapes the overall ponent membrane signaling complex that plays a crucial role in pharmacological sensitivities of the Nav channel signaling com- cellular excitability. Although the mechanism remains unclear, plex remains unexplored. However, altered ligand interactions β-subunits modify Nav channel function and cause debilitating dis- maybeexploitedtodetectthepresenceofβ4 in normal or orders when mutated. While investigating whether β-subunits also pathological conditions (29). Here, we investigated whether fl β in uence ligand interactions, we found that 4dramaticallyalters β-subunits influence Nav channel sensitivity to molecules iso- toxin binding to Nav1.2. To explore these observations further, we lated from animal venom and discovered that β4 can drastically β solved the crystal structure of the extracellular 4 domain and iden- alter the response of the neuronal Nav1.2 isoform to spider and fi 58 ti ed Cys as an exposed residue that, when mutated, eliminates scorpion toxins that target paddle motifs within Nav channel voltage the influence of β4 on toxin pharmacology. Moreover, our results sensors. To elucidate the machinery underlying this observation, we suggest the presence of a docking site that is maintained by a cyste- solved the crystal structure of the extracellular β4 domain and found β 58 ine bridge buried within the hydrophobic core of 4. Disrupting this a Cys-containing binding interface that is involved in Nav channel bridge by introducing a β1 mutation implicated in epilepsy reposi- modulation of toxin pharmacology by β4. Remarkably, dismantling 58 tions the Cys-containing loop and disrupts β4 modulation of Nav1.2. the strictly conserved internal cysteine bridge in β4 by introducing Overall, the principles emerging from this work (i) help explain tissue- a β1 mutation implicated in epilepsy (30) does not preclude protein dependent variations in Nav channel pharmacology; (ii) enable the folding and trafficking to the membrane. However, conformational mechanistic interpretation of β-subunit–related disorders; and (iii) changes induced by the mutation perturb the 58Cys-containing loop PHYSIOLOGY provide insights in designing molecules capable of correcting aber- and disrupt β4 interaction with Nav1.2, in turn altering the func- β rant -subunit behavior. tional and pharmacological properties of the larger Nav channel signaling complex. voltage-gated sodium channel | beta4 subunit | ProTx-II | X-ray structure | disease mutations Results β-Subunits Shape Nav Channel Pharmacology. Although the influence of β-subunits on ion channel gating is well documented (5), little is oltage-gated sodium (Nav) channels play a key role in cel- Vlular communication by manipulating the transmembrane known about their ability to manipulate the pharmacological voltage gradient to encode and propagate vital information rapidly sensitivities of Nav channel signaling complexes (29, 31, 32). To investigate the extent to which these versatile glycoproteins modify over long distances (1). Consequently, mutations that modify Nav channel activity underlie debilitating neurological diseases, mus- ligand interactions, we applied seven toxins from spider, scorpion, sea anemone, and wasp venom (ProTx-I, ProTx-II, TsVII, AaHII, cular disorders, and pain syndromes (2, 3). Typically, Nav channels are part of a membrane-embedded signaling complex that involves various integral membrane proteins (4). The significance of this Significance environment for proper channel function is highlighted by di- vergent Nav channel responses to changes in membrane voltage Voltage-gated sodium (Nav) channels are members of a large when expressed in native tissues or in heterologous systems. complex that plays a crucial role in rapid electrical signaling β-Subunits are prominent members of the Nav channel signaling throughout the human body. As prominent members of this β complex but do not contribute to the ion-conducting pore (5). complex, -subunits modify Nav channel function and cause Instead, they are multifunctional single-transmembrane segment debilitating disorders when mutated. Collectively, the func- glycoproteins that (i) modulate the gating properties of voltage- tional and crystallographic results reported in this work uncover gated ion channels; (ii)regulateNav channel trafficking and ex- intricate interactions of these elements within the Nav-channel pression levels; and (iii) promote cell adhesion and migration (5– signaling complex and establish a key role for β-subunits in 14). Of the four known β-subunits and their splice variants (15–20), shaping Nav1.2 pharmacology. An important concept emerging β4 is unique in that it enables resurgent current, a feature that from our results is that β-subunits provide exciting opportuni- ties for designing new therapeutic strategies to correct their renders certain Nav channel isoforms capable of high-frequency firing in excitable tissues (21). Moreover, aberrant behavior of the abnormal behaviors. ubiquitously expressed β4 subunit has been implicated in long-QT Author contributions: J.G., S.D., F.V.P., and F.B. designed research, performed research, syndrome (LQTS) (22), LQTS-associated Sudden Infant Death analyzed data, and wrote the paper. Syndrome (23), atrial fibrillation (24), Huntington’s disease (25), The authors declare no conflict of interest. and prostate cancer (26), possibly through dysregulation of the Nav channel signaling complex. β4 also is targeted by β-andγ-secretase This article is a PNAS Direct Submission. enzymes from the amyloidogenic pathway, a recent observation Data deposition: Crystallography, atomic coordinates, and structure factors reported in this paper have been deposited in the Protein Data Bank, www.pdb.org (PDB ID codes that suggests a potential contribution of this particular subunit to 4MZ2 and 4MZ3). ’ the development of Alzheimer s disease (27). 1J.G. and S.D. contributed equally to this work. Despite accumulating evidence supporting an important con- 2To whom correspondence may be addressed. E-mail: fi[email protected] or tribution to neuronal excitability and various health disorders [email protected]. (28), fundamental questions about the molecular mechanisms This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. underlying β4 interaction with Nav channels remain unanswered. 1073/pnas.1314557110/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1314557110 PNAS Early Edition | 1of9 Downloaded by guest on October 1, 2021 LqqIV, ATX-II, and β-PMTX) as well as two drugs (lidocaine and Nav1.2 and to inhibit channel opening (34, 35). However, in the β ambroxol) to Xenopus oocytes expressing the neuronal Nav1.2 presence of 4, Nav1.2 is dramatically less inhibited, suggesting isoform and determined potential changes in ligand susceptibility that β4 may prevent ProTx-II from interacting with one or more induced by the presence of each of the four β-subunits. We un- of its receptor sites (Fig. 1B). Second, the structurally unrelated covered multiple conditions in which Nav1.2’s sensitivity to a par- scorpion toxin TsVII promotes Nav channel opening by prefer- ticular toxin was modified by β-subunits, whereas sensitivity to entially interacting with the voltage sensor in domain II and sta- neither drug was significantly affected (Fig. 1, Fig. S1,andTable bilizing it in an activated state (34, 36). Without β-subunits present, S1). For example, the sea anemone toxin ATX-II interacts exclu- 500 nM TsVII causes Nav1.2 to open at more negative voltages, sively with the Nav1.2 domain IV voltage sensor to inhibit fast although the maximal conductance of the channel is not affected. inactivation, resulting in a large increase in inward sodium ion flow In contrast, TsVII greatly decreases Nav1.2 maximal conductance (33). When β2 is present, 100 nM ATX-II still prevents Na 1.2 from with a smaller shift in activation voltage when β4 is present (Fig. v C β fl inactivating rapidly; however, the peak sodium current increases 1 ), raising the possibility that this -subunit exerts an in uence on only marginally (Fig. S1). A similar effect is seen when 100 nM of the domain II voltage sensor. Next, we crystallized the extracellular β fl the domain IV-targeting scorpion toxin LqqIV is applied to Na 1.2 4 domain to explore the mechanisms underlying the in uence of v β coexpressed with β1 [binding site identification is given in Fig. S2 this particular -subunit on Nav1.2 pharmacology. (34)]. In this instance, however, LqqIV also shifts the steady-state The β4 Subunit Structure Reveals an Exposed Cysteine. Despite their inactivation curve to more positive potentials (V from −57 mV 1/2 impact on the functional and pharmacological properties of Na to −48 mV; P ≤ 0.001), thereby increasing channel availability to v channels, tertiary structural information about β-subunits has
Load more

Recommended publications
  • Voltage-Gated Sodium Channel Β1/Β1b Subunits Regulate Cardiac Physiology and Pathophysiology
    MINI REVIEW published: 23 April 2018 doi: 10.3389/fphys.2018.00351 Voltage-Gated Sodium Channel β1/β1B Subunits Regulate Cardiac Physiology and Pathophysiology Nnamdi Edokobi and Lori L. Isom* Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, United States Cardiac myocyte contraction is initiated by a set of intricately orchestrated electrical impulses, collectively known as action potentials (APs). Voltage-gated sodium channels (NaVs) are responsible for the upstroke and propagation of APs in excitable cells, including cardiomyocytes. NaVs consist of a single, pore-forming α subunit and two different β subunits. The β subunits are multifunctional cell adhesion molecules and channel modulators that have cell type and subcellular domain specific functional effects. Variants in SCN1B, the gene encoding the Nav-β1 and -β1B subunits, are linked to atrial and ventricular arrhythmias, e.g., Brugada syndrome, as well as to the early infantile epileptic encephalopathy Dravet syndrome, all of which put patients at risk for sudden death. Evidence over the past two decades has demonstrated that Nav-β1/β1B subunits play critical roles in cardiac myocyte physiology, in which they regulate tetrodotoxin-resistant and -sensitive sodium currents, potassium currents, and calcium handling, and that Na -β1/β1B subunit dysfunction generates substrates Edited by: v Hugues Abriel, for arrhythmias. This review will highlight the role of Nav-β1/β1B subunits in cardiac Universität Bern, Switzerland physiology and pathophysiology. Reviewed by: Thomas Jespersen, Keywords: sodium channel, B subunit, arrhythmia, epilepsy, cell adhesion, electrophysiology University of Copenhagen, Denmark Steve Poelzing, Virginia Tech, United States INTRODUCTION *Correspondence: Lori L. Isom The heart contracts to pump blood throughout the body.
    [Show full text]
  • 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.
    [Show full text]
  • Towards Mutation-Specific Precision Medicine in Atypical Clinical
    International Journal of Molecular Sciences Review Towards Mutation-Specific Precision Medicine in Atypical Clinical Phenotypes of Inherited Arrhythmia Syndromes Tadashi Nakajima * , Shuntaro Tamura, Masahiko Kurabayashi and Yoshiaki Kaneko Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, Maebashi 371-8511, Gunma, Japan; [email protected] (S.T.); [email protected] (M.K.); [email protected] (Y.K.) * Correspondence: [email protected]; Tel.: +81-27-220-8145; Fax: +81-27-220-8158 Abstract: Most causal genes for inherited arrhythmia syndromes (IASs) encode cardiac ion channel- related proteins. Genotype-phenotype studies and functional analyses of mutant genes, using heterol- ogous expression systems and animal models, have revealed the pathophysiology of IASs and enabled, in part, the establishment of causal gene-specific precision medicine. Additionally, the utilization of induced pluripotent stem cell (iPSC) technology have provided further insights into the patho- physiology of IASs and novel promising therapeutic strategies, especially in long QT syndrome. It is now known that there are atypical clinical phenotypes of IASs associated with specific mutations that have unique electrophysiological properties, which raises a possibility of mutation-specific precision medicine. In particular, patients with Brugada syndrome harboring an SCN5A R1632C mutation exhibit exercise-induced cardiac events, which may be caused by a marked activity-dependent loss of R1632C-Nav1.5 availability due to a marked delay of recovery from inactivation. This suggests that the use of isoproterenol should be avoided. Conversely, the efficacy of β-blocker needs to be examined. Patients harboring a KCND3 V392I mutation exhibit both cardiac (early repolarization syndrome and Citation: Nakajima, T.; Tamura, S.; paroxysmal atrial fibrillation) and cerebral (epilepsy) phenotypes, which may be associated with a Kurabayashi, M.; Kaneko, Y.
    [Show full text]
  • Next Generation Sequencing for Molecular Confirmation of Hereditary
    Arch Cardiol Mex. 2015;85(1):68---72 www.elsevier.com.mx SPECIAL ARTICLE Next generation sequencing for molecular confirmation of hereditary sudden cardiac death syndromes a,∗ b b b Manlio F. Márquez , David Cruz-Robles , Selene Ines-Real , Gilberto Vargas-Alarcón , a Manuel Cárdenas a Departamento de Electrofisiología, Instituto Nacional de Cardiología Ignacio Chávez, México, D.F., Mexico b Departamento de Biología Molecular, Instituto Nacional de Cardiología Ignacio Chávez, México, D.F., Mexico Received 26 March 2014; accepted 8 December 2014 KEYWORDS Abstract Hereditary sudden cardiac death syndromes comprise a wide range of diseases result- Arrhythmias; ing from alteration in cardiac ion channels. Genes involved in these syndromes represent diverse Hereditary sudden mutations that cause the altered encoding of the diverse proteins constituting these channels, cardiac death thus affecting directly the currents of the corresponding ions. In the present article we will syndromes; briefly review how to arrive to a clinical diagnosis and we will present the results of molecular Right ventricle genetic studies made in Mexican subjects attending the SCD Syndromes Clinic of the National arrhythmogenic Institute of Cardiology of Mexico City. cardiomyopathy; © 2014 Instituto Nacional de Cardiología Ignacio Chávez. Published by Masson Doyma México Brugada syndrome S.A. All rights reserved. PALABRAS CLAVE Confirmación diagnóstica molecular mediante secuenciación masiva de nueva Arritmias; generación (‘‘next generation sequencing’’) en síndromes hereditarios de muerte Síndromes súbita cardíaca hereditarios de Resumen Los síndromes hereditarios de muerte súbita cardíaca comprenden una amplia gama muerte súbita; Displasia de enfermedades resultantes de la alteración en los canales iónicos cardíacos. Los genes implicados en estos síndromes presentan mutaciones que causan alteraciones de las diversas Arritmogénica del proteínas que constituyen estos canales y que, por lo tanto, afectan directamente a las difer- ventriculo derecho; entes corrientes iónicas.
    [Show full text]
  • Investigating Unexplained Deaths for Molecular Autopsies
    The author(s) shown below used Federal funding provided by the U.S. Department of Justice to prepare the following resource: Document Title: Investigating Unexplained Deaths for Molecular Autopsies Author(s): Yingying Tang, M.D., Ph.D, DABMG Document Number: 255135 Date Received: August 2020 Award Number: 2011-DN-BX-K535 This resource has not been published by the U.S. Department of Justice. This resource is being made publically available through the Office of Justice Programs’ National Criminal Justice Reference Service. Opinions or points of view expressed are those of the author(s) and do not necessarily reflect the official position or policies of the U.S. Department of Justice. Final Technical Report NIJ FY 11 Basic Science Research to Support Forensic Science 2011-DN-BX-K535 Investigating Unexplained Deaths through Molecular Autopsies May 28, 2017 Yingying Tang, MD, PhD, DABMG Principal Investigator Director, Molecular Genetics Laboratory Office of Chief Medical Examiner 421 East 26th Street New York, NY, 10016 Tel: 212-323-1340 Fax: 212-323-1540 Email: [email protected] Page 1 of 41 This resource was prepared by the author(s) using Federal funds provided by the U.S. Department of Justice. Opinions or points of view expressed are those of the author(s) and do not necessarily reflect the official position or policies of the U.S. Department of Justice. Abstract Sudden Unexplained Death (SUD) is natural death in a previously healthy individual whose cause remains undetermined after scene investigation, complete autopsy, and medical record review. SUD affects children and adults, devastating families, challenging medical examiners, and is a focus of research for cardiologists, neurologists, clinical geneticists, and scientists.
    [Show full text]
  • Kchip2 Is a Core Transcriptional Regulator of Cardiac Excitability
    RESEARCH ARTICLE KChIP2 is a core transcriptional regulator of cardiac excitability Drew M Nassal1,2, Xiaoping Wan1, Haiyan Liu1, Danielle Maleski1, Angelina Ramirez-Navarro1, Christine S Moravec3, Eckhard Ficker1†, Kenneth R Laurita1, Isabelle Descheˆ nes1,2* 1Heart and Vascular Research Center, Department of Medicine, Case Western Reserve University, Cleveland, United States; 2Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, United States; 3Department of Molecular Cardiology, Cleveland Clinic, Cleveland, United States Abstract Arrhythmogenesis from aberrant electrical remodeling is a primary cause of death among patients with heart disease. Amongst a multitude of remodeling events, reduced expression of the ion channel subunit KChIP2 is consistently observed in numerous cardiac pathologies. However, it remains unknown if KChIP2 loss is merely a symptom or involved in disease development. Using rat and human derived cardiomyocytes, we identify a previously unobserved transcriptional capacity for cardiac KChIP2 critical in maintaining electrical stability. Through interaction with genetic elements, KChIP2 transcriptionally repressed the miRNAs miR-34b and I I miR-34c, which subsequently targeted key depolarizing ( Na) and repolarizing ( to) currents altered in cardiac disease. Genetically maintaining KChIP2 expression or inhibiting miR-34 under pathologic conditions restored channel function and moreover, prevented the incidence of reentrant arrhythmias. This identifies the KChIP2/miR-34 axis as a central regulator in developing electrical dysfunction and reveals miR-34 as a therapeutic target for treating arrhythmogenesis in heart disease. DOI: 10.7554/eLife.17304.001 *For correspondence: isabelle. [email protected] †Deceased Competing interests: The Introduction authors declare that no Cardiac excitability is controlled by a combination of depolarizing and repolarizing currents, whose competing interests exist.
    [Show full text]
  • Non-Coding Rnas in the Cardiac Action Potential and Their Impact on Arrhythmogenic Cardiac Diseases
    Review Non-Coding RNAs in the Cardiac Action Potential and Their Impact on Arrhythmogenic Cardiac Diseases Estefania Lozano-Velasco 1,2 , Amelia Aranega 1,2 and Diego Franco 1,2,* 1 Cardiovascular Development Group, Department of Experimental Biology, University of Jaén, 23071 Jaén, Spain; [email protected] (E.L.-V.); [email protected] (A.A.) 2 Fundación Medina, 18016 Granada, Spain * Correspondence: [email protected] Abstract: Cardiac arrhythmias are prevalent among humans across all age ranges, affecting millions of people worldwide. While cardiac arrhythmias vary widely in their clinical presentation, they possess shared complex electrophysiologic properties at cellular level that have not been fully studied. Over the last decade, our current understanding of the functional roles of non-coding RNAs have progressively increased. microRNAs represent the most studied type of small ncRNAs and it has been demonstrated that miRNAs play essential roles in multiple biological contexts, including normal development and diseases. In this review, we provide a comprehensive analysis of the functional contribution of non-coding RNAs, primarily microRNAs, to the normal configuration of the cardiac action potential, as well as their association to distinct types of arrhythmogenic cardiac diseases. Keywords: cardiac arrhythmia; microRNAs; lncRNAs; cardiac action potential Citation: Lozano-Velasco, E.; Aranega, A.; Franco, D. Non-Coding RNAs in the Cardiac Action Potential 1. The Electrical Components of the Adult Heart and Their Impact on Arrhythmogenic The adult heart is a four-chambered organ that propels oxygenated blood to the entire Cardiac Diseases. Hearts 2021, 2, body. It is composed of atrial and ventricular chambers, each of them with distinct left and 307–330.
    [Show full text]
  • Mapping Protein Interactions of Sodium Channel Nav1.7 Using 2 Epitope-Tagged Gene Targeted Mice
    bioRxiv preprint doi: https://doi.org/10.1101/118497; this version posted March 20, 2017. 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. 1 Mapping protein interactions of sodium channel NaV1.7 using 2 epitope-tagged gene targeted mice 3 Alexandros H. Kanellopoulos1†, Jennifer Koenig1, Honglei Huang2, Martina Pyrski3, 4 Queensta Millet1, Stephane Lolignier1, Toru Morohashi1, Samuel J. Gossage1, Maude 5 Jay1, John Linley1, Georgios Baskozos4, Benedikt Kessler2, James J. Cox1, Frank 6 Zufall3, John N. Wood1* and Jing Zhao1†** 7 1Molecular Nociception Group, WIBR, University College London, Gower Street, 8 London WC1E 6BT, UK. 9 2Mass Spectrometry Laboratory, Target Discovery Institute, University of Oxford, The 10 Old Road Campus, Oxford, OX3 7FZ, UK. 11 3Center for Integrative Physiology and Molecular Medicine, Saarland University, 12 Kirrbergerstrasse, Bldg. 48, 66421 Homburg, Germany. 13 4Division of Bioscience, University College London, Gower Street, London WC1E 6BT, UK.14 15 †These authors contributed equally to directing this work. 16 *Correspondence author. Tel: +44 207 6796 954; E-mail: [email protected] 17 **Corresponding author: Tel: +44 207 6790 959; E-mail: [email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/118497; this version posted March 20, 2017. 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. 18 Abstract 19 The voltage-gated sodium channel NaV1.7 plays a critical role in pain pathways. 20 Besides action potential propagation, NaV1.7 regulates neurotransmitter release, 21 integrates depolarizing inputs over long periods and regulates transcription.
    [Show full text]
  • Atrial Fibrillation (ATRIA) Study
    European Journal of Human Genetics (2014) 22, 297–306 & 2014 Macmillan Publishers Limited All rights reserved 1018-4813/14 www.nature.com/ejhg REVIEW Atrial fibrillation: the role of common and rare genetic variants Morten S Olesen*,1,2,4, Morten W Nielsen1,2,4, Stig Haunsø1,2,3 and Jesper H Svendsen1,2,3 Atrial fibrillation (AF) is the most common cardiac arrhythmia affecting 1–2% of the general population. A number of studies have demonstrated that AF, and in particular lone AF, has a substantial genetic component. Monogenic mutations in lone and familial AF, although rare, have been recognized for many years. Presently, mutations in 25 genes have been associated with AF. However, the complexity of monogenic AF is illustrated by the recent finding that both gain- and loss-of-function mutations in the same gene can cause AF. Genome-wide association studies (GWAS) have indicated that common single-nucleotide polymorphisms (SNPs) have a role in the development of AF. Following the first GWAS discovering the association between PITX2 and AF, several new GWAS reports have identified SNPs associated with susceptibility of AF. To date, nine SNPs have been associated with AF. The exact biological pathways involving these SNPs and the development of AF are now starting to be elucidated. Since the first GWAS, the number of papers concerning the genetic basis of AF has increased drastically and the majority of these papers are for the first time included in a review. In this review, we discuss the genetic basis of AF and the role of both common and rare genetic variants in the susceptibility of developing AF.
    [Show full text]
  • Identification of Key Genes and Pathways Involved in Response To
    Deng et al. Biol Res (2018) 51:25 https://doi.org/10.1186/s40659-018-0174-7 Biological Research RESEARCH ARTICLE Open Access Identifcation of key genes and pathways involved in response to pain in goat and sheep by transcriptome sequencing Xiuling Deng1,2†, Dong Wang3†, Shenyuan Wang1, Haisheng Wang2 and Huanmin Zhou1* Abstract Purpose: This aim of this study was to investigate the key genes and pathways involved in the response to pain in goat and sheep by transcriptome sequencing. Methods: Chronic pain was induced with the injection of the complete Freund’s adjuvant (CFA) in sheep and goats. The animals were divided into four groups: CFA-treated sheep, control sheep, CFA-treated goat, and control goat groups (n 3 in each group). The dorsal root ganglions of these animals were isolated and used for the construction of a cDNA= library and transcriptome sequencing. Diferentially expressed genes (DEGs) were identifed in CFA-induced sheep and goats and gene ontology (GO) enrichment analysis was performed. Results: In total, 1748 and 2441 DEGs were identifed in CFA-treated goat and sheep, respectively. The DEGs identi- fed in CFA-treated goats, such as C-C motif chemokine ligand 27 (CCL27), glutamate receptor 2 (GRIA2), and sodium voltage-gated channel alpha subunit 3 (SCN3A), were mainly enriched in GO functions associated with N-methyl- D-aspartate (NMDA) receptor, infammatory response, and immune response. The DEGs identifed in CFA-treated sheep, such as gamma-aminobutyric acid (GABA)-related DEGs (gamma-aminobutyric acid type A receptor gamma 3 subunit [GABRG3], GABRB2, and GABRB1), SCN9A, and transient receptor potential cation channel subfamily V member 1 (TRPV1), were mainly enriched in GO functions related to neuroactive ligand-receptor interaction, NMDA receptor, and defense response.
    [Show full text]
  • Cardiogenetics Testing Reference Guide December 2018
    Cardiogenetics Testing reference guide December 2018 Why Choose Ambry More than 1 in 200 people have an inherited cardiovascular condition. Ambry’s mission is to provide the most advanced genetic testing information available to help you identity those at-risk and determine the best treatment options. If we know a patient has a disease-causing genetic change, not only does it mean better disease management, it also indicates that we can test others in the family and provide them with potentially life-saving information. Diseases and Testing Options cardiomyopathies arrhythmias Hypertrophic Cardiomyopathy (HCMNext) Catecholaminergic Polymorphic Ventricular Dilated Cardiomyopathy (DCMNext) Tachycardia (CPVTNext) Arrhythmogenic Right Ventricular Long QT Syndrome, Short QT Syndrome, Cardiomyopathy (ARVCNext) Brugada Syndrome (LongQTNext, RhythmNext) Cardiomyopathies (CMNext, CardioNext) Arrhythmias (RhythmNext, CardioNext) other cardio conditions Transthyretin Amyloidosis (TTR) familial hypercholesterolemia Noonan Syndrome (NoonanNext) and lipid disorders Hereditary Hemorrhagic Telangiectasia Familial Hypercholesterolemia (FHNext) (HHTNext) Sitosterolemia (Sitosterolemia Panel) Comprehensive Lipid Menu thoracic aortic aneurysms (CustomNext-Cardio) and dissections Familial Chylomicronemia Syndrome (FCSNext) Thoracic Aneurysms and Dissections, aortopathies (TAADNext) Marfan Syndrome (TAADNext) Ehlers-Danlos Syndrome (TAADNext) Targeted Panels Gene Comparison ALL PANELS HAVE A TURNAROUND TIME OF 2-3 WEEKS arrhythmias CPVTNext CPVTNext CASQ2,
    [Show full text]
  • Singular Localization of Sodium Channel &Beta
    ARTICLE Received 2 May 2014 | Accepted 9 Oct 2014 | Published 21 Nov 2014 DOI: 10.1038/ncomms6525 Singular localization of sodium channel b4 subunit in unmyelinated fibres and its role in the striatum Haruko Miyazaki1,2,3,4, Fumitaka Oyama2,5, Ritsuko Inoue6, Toshihiko Aosaki6, Takaya Abe7, Hiroshi Kiyonari7, Yoshihiro Kino1,2,3,4, Masaru Kurosawa1,2,3,4, Jun Shimizu8, Ikuo Ogiwara9, Kazuhiro Yamakawa9, Yoshinori Koshimizu10, Fumino Fujiyama4,10,11, Takeshi Kaneko10, Hideaki Shimizu12, Katsuhiro Nagatomo13, Katsuya Yamada13, Tomomi Shimogori3, Nobutaka Hattori14, Masami Miura6 & Nobuyuki Nukina1,2,3,4 Voltage-gated Na þ channel b-subunits are multifunctional molecules that modulate Na þ channel activity and regulate cell adhesion, migration and neurite outgrowth. b-subunits including b4 are known to be highly concentrated in the nodes of Ranvier and axon initial segments in myelinated axons. Here we show diffuse b4 localization in striatal projection fibres using transgenic mice that express fluorescent protein in those fibres. These axons are unmyelinated, forming large, inhibitory fibre bundles. Furthermore, we report b4 dimer expression in the mouse brain, with high levels of b4 dimers in the striatal projection fascicles, suggesting a specific role of b4 in those fibres. Scn4b-deficient mice show a resurgent Na þ current reduction, decreased repetitive firing frequency in medium spiny neurons and increased failure rates of inhibitory postsynaptic currents evoked with repetitive stimulation, indicating an in vivo channel regulatory role of b4 in the striatum. 1 Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
    [Show full text]