Purinergic Signaling Controls Spontaneous Activity in the Auditory System Throughout Early Development
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Single-Cell Rnaseq Reveals Seven Classes of Colonic Sensory Neuron
Gut Online First, published on February 26, 2018 as 10.1136/gutjnl-2017-315631 Neurogastroenterology ORIGINAL ARTICLE Gut: first published as 10.1136/gutjnl-2017-315631 on 26 February 2018. Downloaded from Single-cell RNAseq reveals seven classes of colonic sensory neuron James R F Hockley,1,2 Toni S Taylor,1 Gerard Callejo,1 Anna L Wilbrey,2 Alex Gutteridge,2 Karsten Bach,1 Wendy J Winchester,2 David C Bulmer,1 Gordon McMurray,2 Ewan St John Smith1 ► Additional material is ABSTRact pathways to the central nervous system (CNS).1 In published online only. To view Objective Integration of nutritional, microbial and the colorectum, sensory innervation is organised please visit the journal online (http:// dx. doi. org/ 10. 1136/ inflammatory events along the gut-brain axis can alter into two main pathways: thoracolumbar (TL) spinal gutjnl- 2017- 315631). bowel physiology and organism behaviour. Colonic afferents projecting via the lumbar splanchnic sensory neurons activate reflex pathways and give nerve (LSN) and lumbosacral (LS) spinal afferents 1Department of Pharmacology, University of Cambridge, rise to conscious sensation, but the diversity and projecting via the pelvic nerve (PN) that are respon- Cambridge, UK division of function within these neurons is poorly sible for transducing conscious sensations of full- 2Neuroscience and Pain understood. The identification of signalling pathways ness, discomfort, urgency and pain, in addition to Research Unit, Pfizer, contributing to visceral sensation is constrained by a reflex actions.2 Cambridge, UK paucity of molecular markers. Here we address this by Visceral sensory afferents act to maintain many comprehensive transcriptomic profiling and unsupervised aspects of GI physiology, such as continence and Correspondence to James R F Hockley, Department clustering of individual mouse colonic sensory neurons. -
Mechanisms of Acetylcholine Receptor Loss in Myasthenia Gravis
J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.43.7.601 on 1 July 1980. Downloaded from Journal of Neurology, Neurosurgery, and Psychiatry, 1980, 43, 601-610 Mechanisms of acetylcholine receptor loss in myasthenia gravis DANIEL B DRACHMAN, ROBERT N ADAMS, ELIS F STANLEY, AND ALAN PESTRONK From the Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA SUMMARY The fundamental abnormality affecting the neuromuscular junctions of myasthenic patients is a reduction of available AChRs, due to an autoimmune attack directed against the receptors. Antibodies to AChR are present in most patients, and there is evidence that they have a predominant pathogenic role in the disease, aided by complement. The mechanism of antibody action involves acceleration of the rate of degradation of AChRs, attributable to cross-linking of the receptors. In addition, antibodies may block AChRs, and may participate in producing destructive changes, perhaps in conjunction with complement. The possibility that cell-mediated mechanisms may play a role in the autoimmune responses of some myasthenic patients remains to be explored. Although the target of the autoimmune attack in myasthenic patients is probably always the acetyl- Protected by copyright. choline receptors, it is not yet clear which of these immune mechanisms are most important. It is likely that the relative role of each mechanism varies from patient to patient. One of the goals of future research will be to identify the relative importance of each -
Protease Effects on the Structure of Acetylcholine Receptor Membranes from Torpedo Californica
PROTEASE EFFECTS ON THE STRUCTURE OF ACETYLCHOLINE RECEPTOR MEMBRANES FROM TORPEDO CALIFORNICA MICHAEL W. KLYMKOWSKY, JOHN E . HEUSER, and ROBERT M. STROUD From the Department of Biochemistry & Biophysics, University of California at San Francisco, San Francisco, California 94143 . Dr . Klymkowsky's present address is MRC Neuroimmunology Project, Department of Zoology, University College London, London WC IE, 6BT, England ABSTRACT Protease digestion of acetylcholine receptor-rich membranes derived from Torpedo californica electroplaques by homogenization and isopycnic centrifugation results in degradation of all receptor subunits without any significant effect on the appearance in electron micrographs, the toxin binding ability, or the sedimentation value of the receptor molecule . Such treatment does produce dramatic changes in the morphology of the normally 0.5- to 2-lm-diameter spherical vesicles when observed by either negative-stain or freeze-fracture electron microscopy . Removal of peripheral, apparently nonreceptor polypeptides by alkali stripping (Neubig et al ., 1979, Proc. Natl. Acad. Sci. U. S. A. 76:690-694) results in increased sensitivity of the acetylcholine receptor membranes to the protease trypsin as indicated by SDS gel electrophoretic patterns and by the extent of morphologic change observed in vesicle structure . Trypsin digestion of alkali-stripped receptor membranes results in a limit degradation pattern of all four receptor subunits, whereupon all the vesicles undergo the morphological transformation to minivesicles -
Interplay Between Gating and Block of Ligand-Gated Ion Channels
brain sciences Review Interplay between Gating and Block of Ligand-Gated Ion Channels Matthew B. Phillips 1,2, Aparna Nigam 1 and Jon W. Johnson 1,2,* 1 Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA; [email protected] (M.B.P.); [email protected] (A.N.) 2 Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA * Correspondence: [email protected]; Tel.: +1-(412)-624-4295 Received: 27 October 2020; Accepted: 26 November 2020; Published: 1 December 2020 Abstract: Drugs that inhibit ion channel function by binding in the channel and preventing current flow, known as channel blockers, can be used as powerful tools for analysis of channel properties. Channel blockers are used to probe both the sophisticated structure and basic biophysical properties of ion channels. Gating, the mechanism that controls the opening and closing of ion channels, can be profoundly influenced by channel blocking drugs. Channel block and gating are reciprocally connected; gating controls access of channel blockers to their binding sites, and channel-blocking drugs can have profound and diverse effects on the rates of gating transitions and on the stability of channel open and closed states. This review synthesizes knowledge of the inherent intertwining of block and gating of excitatory ligand-gated ion channels, with a focus on the utility of channel blockers as analytic probes of ionotropic glutamate receptor channel function. Keywords: ligand-gated ion channel; channel block; channel gating; nicotinic acetylcholine receptor; ionotropic glutamate receptor; AMPA receptor; kainate receptor; NMDA receptor 1. Introduction Neuronal information processing depends on the distribution and properties of the ion channels found in neuronal membranes. -
Cellular Trafficking of Nicotinic Acetylcholine Receptors
npg Acta Pharmacol Sin 2009 Jun; 30 (6): 656–662 Review Cellular trafficking of nicotinic acetylcholine receptors Paul A ST JOHN* Department of Cell Biology and Anatomy, University of Arizona College of Medicine, Tucson, AZ 85724, USA Nicotinic acetylcholine receptors (nAChRs) play critical roles throughout the body. Precise regulation of the cellular loca- tion and availability of nAChRs on neurons and target cells is critical to their proper function. Dynamic, post-translational regulation of nAChRs, particularly control of their movements among the different compartments of cells, is an important aspect of that regulation. A combination of new information and new techniques has the study of nAChR trafficking poised for new breakthroughs. Keywords: membrane traffic; protein traffic; biosynthesis; endocytosis; endoplasmic reticulum-associated degradation Acta Pharmacologica Sinica (2009) 30: 656–662; doi: 10.1038/aps.2009.76 Introduction ways, but two particular perturbations have been especially well studied and exert their effects at least in part by altering Nicotinic acetylcholine receptors (nAChRs) mediate the trafficking of nAChRs: 1) denervation changes the total synaptic transmission in the CNS, in autonomic ganglia, and number, the distribution, and the turnover rate of nAChRs in at neuromuscular junctions and other peripheral synapses. skeletal muscle; 2) prolonged exposure to nicotine increases The functional properties of these synapses differ, but in each the total number of nAChRs in neurons. Several of the stud- case, properly functional signaling requires cellular control ies reviewed here addressed the mechanisms by which these of the number, type, and location of nAChRs. Trafficking treatments alter nAChR trafficking. Other authors in this of nAChRs – the movement of nAChRs between compart- special issue will address other aspects of the effects of nico- ments of a cell, including the cell's biosynthetic and degrada- tine on nAChRs. -
Non-Neuronal Functions of the M2 Muscarinic Acetylcholine Receptor
Genes 2013, 4, 171-197; doi:10.3390/genes4020171 OPEN ACCESS genes ISSN 2073-4425 www.mdpi.com/journal/genes Review Non-Neuronal Functions of the M2 Muscarinic Acetylcholine Receptor Wymke Ockenga, Sina Kühne, Simone Bocksberger, Antje Banning and Ritva Tikkanen * Institute of Biochemistry, Medical Faculty, University of Giessen, Friedrichstrasse 24, 35392 Giessen, Germany; E-Mails: [email protected] (W.O.); [email protected] (S.K.); [email protected] (S.B.); [email protected] (A.B.) * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +49-641-9947-420; Fax: +49-641-9947-429. Received: 31 January 2013; in revised form: 10 March 2013 / Accepted: 25 March 2013 / Published: 2 April 2013 Abstract: Acetylcholine is an important neurotransmitter whose effects are mediated by two classes of receptors. The nicotinic acetylcholine receptors are ion channels, whereas the muscarinic receptors belong to the large family of G protein coupled seven transmembrane helix receptors. Beyond its function in neuronal systems, it has become evident that acetylcholine also plays an important role in non-neuronal cells such as epithelial and immune cells. Furthermore, many cell types in the periphery are capable of synthesizing acetylcholine and express at least some of the receptors. In this review, we summarize the non-neuronal functions of the muscarinic acetylcholine receptors, especially those of the M2 muscarinic receptor in epithelial cells. We will review the mechanisms of signaling by the M2 receptor but also the cellular trafficking and ARF6 mediated endocytosis of this receptor, which play an important role in the regulation of signaling events. -
Supplementary Table 1. Pain and PTSS Associated Genes (N = 604
Supplementary Table 1. Pain and PTSS associated genes (n = 604) compiled from three established pain gene databases (PainNetworks,[61] Algynomics,[52] and PainGenes[42]) and one PTSS gene database (PTSDgene[88]). These genes were used in in silico analyses aimed at identifying miRNA that are predicted to preferentially target this list genes vs. a random set of genes (of the same length). ABCC4 ACE2 ACHE ACPP ACSL1 ADAM11 ADAMTS5 ADCY5 ADCYAP1 ADCYAP1R1 ADM ADORA2A ADORA2B ADRA1A ADRA1B ADRA1D ADRA2A ADRA2C ADRB1 ADRB2 ADRB3 ADRBK1 ADRBK2 AGTR2 ALOX12 ANO1 ANO3 APOE APP AQP1 AQP4 ARL5B ARRB1 ARRB2 ASIC1 ASIC2 ATF1 ATF3 ATF6B ATP1A1 ATP1B3 ATP2B1 ATP6V1A ATP6V1B2 ATP6V1G2 AVPR1A AVPR2 BACE1 BAMBI BDKRB2 BDNF BHLHE22 BTG2 CA8 CACNA1A CACNA1B CACNA1C CACNA1E CACNA1G CACNA1H CACNA2D1 CACNA2D2 CACNA2D3 CACNB3 CACNG2 CALB1 CALCRL CALM2 CAMK2A CAMK2B CAMK4 CAT CCK CCKAR CCKBR CCL2 CCL3 CCL4 CCR1 CCR7 CD274 CD38 CD4 CD40 CDH11 CDK5 CDK5R1 CDKN1A CHRM1 CHRM2 CHRM3 CHRM5 CHRNA5 CHRNA7 CHRNB2 CHRNB4 CHUK CLCN6 CLOCK CNGA3 CNR1 COL11A2 COL9A1 COMT COQ10A CPN1 CPS1 CREB1 CRH CRHBP CRHR1 CRHR2 CRIP2 CRYAA CSF2 CSF2RB CSK CSMD1 CSNK1A1 CSNK1E CTSB CTSS CX3CL1 CXCL5 CXCR3 CXCR4 CYBB CYP19A1 CYP2D6 CYP3A4 DAB1 DAO DBH DBI DICER1 DISC1 DLG2 DLG4 DPCR1 DPP4 DRD1 DRD2 DRD3 DRD4 DRGX DTNBP1 DUSP6 ECE2 EDN1 EDNRA EDNRB EFNB1 EFNB2 EGF EGFR EGR1 EGR3 ENPP2 EPB41L2 EPHB1 EPHB2 EPHB3 EPHB4 EPHB6 EPHX2 ERBB2 ERBB4 EREG ESR1 ESR2 ETV1 EZR F2R F2RL1 F2RL2 FAAH FAM19A4 FGF2 FKBP5 FLOT1 FMR1 FOS FOSB FOSL2 FOXN1 FRMPD4 FSTL1 FYN GABARAPL1 GABBR1 GABBR2 GABRA2 GABRA4 -
Transcriptomes and Neurotransmitter Profiles of Classes of Gustatory And
ARTICLE DOI: 10.1038/s41467-017-01095-1 OPEN Transcriptomes and neurotransmitter profiles of classes of gustatory and somatosensory neurons in the geniculate ganglion Gennady Dvoryanchikov 1, Damian Hernandez1, Jennifer K. Roebber 2, David L. Hill3, Stephen D. Roper 1,2,4 & Nirupa Chaudhari 1,2,4 Taste buds are innervated by neurons whose cell bodies reside in cranial sensory ganglia. Studies on the functional properties and connectivity of these neurons are hindered by the lack of markers to define their molecular identities and classes. The mouse geniculate ganglion contains chemosensory neurons innervating lingual and palatal taste buds and somatosensory neurons innervating the pinna. Here, we report single cell RNA sequencing of geniculate ganglion neurons. Using unbiased transcriptome analyses, we show a pronounced separation between two major clusters which, by anterograde labeling, correspond to gus- tatory and somatosensory neurons. Among the gustatory neurons, three subclusters are present, each with its own complement of transcription factors and neurotransmitter response profiles. The smallest subcluster expresses both gustatory- and mechanosensory- related genes, suggesting a novel type of sensory neuron. We identify several markers to help dissect the functional distinctions among gustatory neurons and address questions regarding target interactions and taste coding. 1 Department of Physiology & Biophysics, University of Miami Miller School of Medicine, Miami, FL 33136, USA. 2 Graduate Program in Neurosciences, University of Miami Miller School of Medicine, Miami, FL 33136, USA. 3 Department of Psychology, University of Virginia, Charlottesville, VA 22904, USA. 4 Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, USA. Gennady Dvoryanchikov and Damian Hernandez contributed equally to the work. -
Modulatory Roles of ATP and Adenosine in Cholinergic Neuromuscular Transmission
International Journal of Molecular Sciences Review Modulatory Roles of ATP and Adenosine in Cholinergic Neuromuscular Transmission Ayrat U. Ziganshin 1,* , Adel E. Khairullin 2, Charles H. V. Hoyle 1 and Sergey N. Grishin 3 1 Department of Pharmacology, Kazan State Medical University, 49 Butlerov Street, 420012 Kazan, Russia; [email protected] 2 Department of Biochemistry, Laboratory and Clinical Diagnostics, Kazan State Medical University, 49 Butlerov Street, 420012 Kazan, Russia; [email protected] 3 Department of Medical and Biological Physics with Computer Science and Medical Equipment, Kazan State Medical University, 49 Butlerov Street, 420012 Kazan, Russia; [email protected] * Correspondence: [email protected]; Tel.: +7-843-236-0512 Received: 30 June 2020; Accepted: 1 September 2020; Published: 3 September 2020 Abstract: A review of the data on the modulatory action of adenosine 5’-triphosphate (ATP), the main co-transmitter with acetylcholine, and adenosine, the final ATP metabolite in the synaptic cleft, on neuromuscular transmission is presented. The effects of these endogenous modulators on pre- and post-synaptic processes are discussed. The contribution of purines to the processes of quantal and non- quantal secretion of acetylcholine into the synaptic cleft, as well as the influence of the postsynaptic effects of ATP and adenosine on the functioning of cholinergic receptors, are evaluated. As usual, the P2-receptor-mediated influence is minimal under physiological conditions, but it becomes very important in some pathophysiological situations such as hypothermia, stress, or ischemia. There are some data demonstrating the same in neuromuscular transmission. It is suggested that the role of endogenous purines is primarily to provide a safety factor for the efficiency of cholinergic neuromuscular transmission. -
Effects of the Histamine H3 Receptor Antagonist ABT-239 on Cognition
Pharmacological Reports Copyright © 2012 2012, 64, 13161325 by Institute of Pharmacology ISSN 1734-1140 Polish Academy of Sciences EffectsofthehistamineH3 receptorantagonist ABT-239oncognitionandnicotine-induced memoryenhancementinmice MartaKruk1,JoannaMiszkiel2,AndrewC.McCreary3, EdmundPrzegaliñski2,Ma³gorzataFilip2,4,Gra¿ynaBia³a1 1 DepartmentofPharmacologyandPharmacodynamics,MedicalUniversityofLublin,ChodŸki4A, PL20-093Lublin,Poland 2 LaboratoryofDrugAddictionPharmacology,InstituteofPharmacology,PolishAcademyofSciences,Smêtna12, PL31-343Kraków,Poland 3 BrainsOn-Line,deMudden16,9747AWGroningen,TheNetherlands 4 DepartmentofToxicology,FacultyofPharmacy,JagiellonianUniversity,CollegeofMedicine,Medyczna9, PL30-688Kraków,Poland Correspondence: Gra¿ynaBia³a,e-mail:[email protected] Abstract: Background: The strong correlation between central histaminergic and cholinergic pathways on cognitive processes has been re- ported extensively. However, the role of histamine H3 receptor mechanisms interacting with nicotinic mechanisms has not previ- ouslybeen extensivelyinvestigated. Methods: The current study was conducted to determine the interactions of nicotinic and histamine H3 receptor systems with regard to learning and memory function using a modified elevated plus-maze test in mice. In this test, the latency for mice to move from the open arm to the enclosed arm (i.e., transfer latency) was used as an index of memory. We tested whether ABT-239 (4-(2-{2-[(2R)-2- methylpyrrolidinyl]ethyl}-benzofuran-5-yl), an H3 receptor antagonist/inverse -
Specific Labeling of Synaptic Schwann Cells Reveals Unique Cellular And
RESEARCH ARTICLE Specific labeling of synaptic schwann cells reveals unique cellular and molecular features Ryan Castro1,2,3, Thomas Taetzsch1,2, Sydney K Vaughan1,2, Kerilyn Godbe4, John Chappell4, Robert E Settlage5, Gregorio Valdez1,2,6* 1Department of Molecular Biology, Cellular Biology, and Biochemistry, Brown University, Providence, United States; 2Center for Translational Neuroscience, Robert J. and Nancy D. Carney Institute for Brain Science and Brown Institute for Translational Science, Brown University, Providence, United States; 3Neuroscience Graduate Program, Brown University, Providence, United States; 4Fralin Biomedical Research Institute at Virginia Tech Carilion, Roanoke, United States; 5Department of Advanced Research Computing, Virginia Tech, Blacksburg, United States; 6Department of Neurology, Warren Alpert Medical School of Brown University, Providence, United States Abstract Perisynaptic Schwann cells (PSCs) are specialized, non-myelinating, synaptic glia of the neuromuscular junction (NMJ), that participate in synapse development, function, maintenance, and repair. The study of PSCs has relied on an anatomy-based approach, as the identities of cell-specific PSC molecular markers have remained elusive. This limited approach has precluded our ability to isolate and genetically manipulate PSCs in a cell specific manner. We have identified neuron-glia antigen 2 (NG2) as a unique molecular marker of S100b+ PSCs in skeletal muscle. NG2 is expressed in Schwann cells already associated with the NMJ, indicating that it is a marker of differentiated PSCs. Using a newly generated transgenic mouse in which PSCs are specifically labeled, we show that PSCs have a unique molecular signature that includes genes known to play critical roles in *For correspondence: PSCs and synapses. These findings will serve as a springboard for revealing drivers of PSC [email protected] differentiation and function. -
The Human Histamine H3-Receptor: Amolecular Modelling Study of a G-Protein Coupled Receptor
THE HUMAN HISTAMINE H3-RECEPTOR: AMOLECULAR MODELLING STUDY OF A G-PROTEIN COUPLED RECEPTOR Inaugural-Dissertation zur Erlangung des Doktorgrades der Mathematisch-Naturwissenschaftlichen Fakultät der Heinrich-Heine-Universität Düsseldorf vorgelegt von Birgit Schlegel aus Linz, Österreich Düsseldorf 2005 Gedruckt mit der Genehmigung der Mathematisch-Naturwissenschaftlichen Fakultät der Heinrich-Heine-Universität Düsseldorf Referent: Prof. Dr. Dr. h.c. Hans-Dieter Höltje 1. Korreferent: Prof. Dr. Wolfgang Sippl 2. Korreferent: Prof. Dr. Thierry Langer Tag der mündlichen Prüfung: 18. Juli 2005 Part I regarding the molecular dynamics simulation of bovine rhodopsin has been published in the Journal of Molecular Modeling. The original publication of this part is available at www.springerlink.com. Die vorliegende Arbeit wurde von November 2001 bis Mai 2005 am Institut für Pharmazeutische Chemie der Heinrich-Heine-Universität Düsseldorf unter der Betreuung von Prof. Dr. W. Sippl und Prof. Dr. Dr. h.c. H.-D. Höltje angefertigt. Mein besonderer Dank gilt Prof. Dr. Dr. h.c. Hans-Dieter Höltje für die Aufnahme in seinen Arbeitskreis, die sehr guten Rahmenbedingungen, den Ansporn eigene wissenschaftliche Ideen zu verteidigen, sowie eine drei-dimensionale Sicht der Welt der Arzneistoffe, die ich während des Besuchs seiner Vorlesung erlangen konnte. Bei Prof. Dr. Wolfgang Sippl möchte ich mich für die sehr gute Betreuung bedanken, die mir den nötigen Freiraum gelassen hat, eigene Ideen umzusetzen, aber gleichzeitig die Arbeit durch unzählige Diskussionen, Anregungen und Vorschläge in eine erfolgversprechende Richtung gelenkt hat. Neben seinem enormen fachlichen Wissen durfte ich auch von den sehr guten Ressourcen seines Arbeitskreises in Halle profitieren, was viele Aspekte der Arbeit erst ermöglicht hat.