DOCSLIB.ORG

Epigenetic Regulation of Kcna3-Encoding Kv1.3 Potassium Channel by Cereblon Contributes to + Regulation of CD4 T-Cell Activation

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Epigenetic Regulation of Kcna3-Encoding Kv1.3 Potassium Channel by Cereblon Contributes to + Regulation of CD4 T-Cell Activation Epigenetic regulation of Kcna3-encoding Kv1.3 potassium channel by cereblon contributes to + regulation of CD4 T-cell activation Jung-Ah Kanga,1, Sang-Heon Parka,1, Sang Phil Jeonga, Min-Hee Hana, Cho-Rong Leea, Kwang Min Leea, Namhee Kima, Mi-Ryoung Songa, Murim Choib, Michael Yec, Guhung Jungd, Won-Woo Leee, Soo Hyun Eoma, Chul-Seung Parka, and Sung-Gyoo Parka,f,2 aSchool of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea; bDepartment of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea; cSchool of Liberal Arts and Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea; dDepartment of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea; eDepartment of Microbiology and Immunology, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea; and fCell Logistics Research Center, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea Edited by Kenneth M. Murphy, Washington University, St. Louis, MO, and approved June 14, 2016 (received for review February 2, 2015) The role of cereblon (CRBN) in T cells is not well understood. We binding of CRBN to Kcna3 leads to epigenetic modification of generated mice with a deletion in Crbn and found cereblon to be the Kcna3 locus and reduces the expression of Kv1.3. Triggering an important antagonist of T-cell activation. In mice lacking CRBN, of TCR signaling in CRBN-deficient T cells results in (i) in- + CD4 T cells show increased activation and IL-2 production on creased potassium and calcium flux, (ii) increased activation of T-cell receptor stimulation, ultimately resulting in increased potas- transcription factor NF-AT, and (iii) increased production of sium flux and calcium-mediated signaling. CRBN restricts T-cell ac- IL-2. Our data identify CRBN as an important regulator of T-cell tivation via epigenetic modification of Kcna3, which encodes the activation, restricting calcium influx via epigenetic repression Kv1.3 potassium channel required for robust calcium influx in T of Kcna3. cells. CRBN binds directly to conserved DNA elements adjacent to Kcna3 via a previously uncharacterized DNA-binding motif. Conse- Results quently, in the absence of CRBN, the expression of Kv1.3 is dere- CRBN Deficiency Does Not Affect T-Cell Development, but Does pressed, resulting in increased Kv1.3 expression, potassium flux, and + Increase T-Cell Activation. Analysis of the relative levels of CRBN CD4 T-cell hyperactivation. In addition, experimental autoimmune – Crbn transcripts in multiple tissue types using the Novartis BioGPS encephalomyelitis in T-cell specific -deficient mice was exacer- expression array database (biogps.org) (9) suggested that the ex- bated by increased T-cell activation via Kv1.3. Thus, CRBN limits + pression of CRBN mRNA is higher in lymphoid cells, including CD4 T-cell activation via epigenetic regulation of Kv1.3 expression. + CD4 T cells, than in other cell types (Fig. S1A). Thus, we used Crbn gene-targeted mice to examine the effect of CRBN defi- T-cell activation | CRBN | Kv1.3 | calcium flux | potassium flux ciency in T-cell development and activation. First, we confirmed + the loss of CRBN protein from CD4 T cells isolated from Crbn- − − ecent studies have identified cereblon (CRBN) as a thalidomide- deficient (Crbn / ) mice (Fig. 1A). There were no obvious changes binding protein (1, 2). CRBN is expressed in the cytoplasm, R in thymic T-cell development (Fig. 1B). In addition, peripheral nucleus, and peripheral membranes of a wide variety of cells and − − T-cell and B-cell populations in 6- to 8-wk-old Crbn / mice were tissues (1, 3–5). CRBN forms an E3 ubiquitin ligase complex with + − no different from those in 6- to 8-wk-old littermate control (Crbn / ) damaged DNA-binding protein (DDB) 1 and Cul4A, and this + + mice (Fig. 1 C and D and Fig. S2A). Moreover, the Foxp3 CD4 complex is involved in limb outgrowth and controls fibroblast −/− INFLAMMATION Crbn IMMUNOLOGY AND growth factor 8 expression in zebrafish and chicks (1). When T-cell population in the spleens of mice was similar to that thalidomide binds to CRBN, it inhibits formation of the E3 ubiquitin ligase complex, which in turn reduces the activity of the Significance ubiquitin ligase and results in defective limb development (1). Recent work suggests that immunomodulatory drugs (IMiDs) In resting T cells, CRBN normally represses expression of the stimulate increased IL-2 production in T cells by binding to CRBN. Kv1.3 potassium channel by regulating histone modifications This binding alters the substrate specificity of CRBN-containing to prevent hyperactivation of T cells. It does this by controlling ubiquitin ligase complexes (6, 7) even though IMiDs reduce the recruitment of EZH1 to the potassium channel region of overall activity of E3 ubiquitin ligase (1). As a result, binding the Kcna3 gene (or locus). However, lack of CRBN causes up- promotes abnormal degradation of the Ikaros zinc finger proteins 1 regulation of Kv1.3 expression, which in turn increases potas- and 3 (IKZF1 and IKZF3), which in turn increases IL-2 production sium flux, thereby triggering increased calcium flux during in T cells (6–8). However, although the CRBN-mediated effects of T-cell activation. IMiDs are known, the physiological role of CRBN in T cells remains unclear. Author contributions: S.-G.P. conceived of the study; J.-A.K., S.-H.P., M.-R.S., M.C., G.J., Crbn W.-W.L., and S.-G.P. designed research; J.-A.K., S.-H.P., S.P.J., M.-H.H., C.-R.L., N.K., and We deleted the gene from murine T cells to examine the S.-G.P. performed research; K.M.L., S.H.E., and C.-S.P. contributed new reagents/analytic physiological role of CRBN during T-cell activation, with the aim tools; J.-A.K., S.-H.P., S.P.J., M.-H.H., C.-R.L., N.K., M.Y., and S.-G.P. analyzed data; and J.-A.K., of gaining new insight into the regulation of potassium flux M.Y., and S.-G.P. wrote the paper. during T-cell signaling. Deletion of Crbn from T cells led to IL-2 The authors declare no conflict of interest. + production and differentiation of CD4 T cells into Th17 ef- This article is a PNAS Direct Submission. fector cells, as well as worsening of the phenotype associated Freely available online through the PNAS open access option. with experimental autoimmune encephalitis (EAE). CRBN re- 1J.-A.K. and S.-H.P. contributed equally to this work. presses T-cell activation by binding to the chromosomal regions 2To whom correspondence should be addressed. Email: [email protected]. Kcna3 adjacent to the locus, a gene encoding the Kv1.3 potas- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. sium channel, which participates in calcium influx in T cells. The 1073/pnas.1502166113/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1502166113 PNAS | August 2, 2016 | vol. 113 | no. 31 | 8771–8776 Downloaded by guest on September 29, 2021 Fig. 1. CRBN deficiency does not affect T-cell development, but does increase T-cell activation. (A) Loss of CRBN protein expression in CD4+ T cells from Crbn−/− mice was confirmed by immunoblot analysis with an anti-CRBN antibody. (B) T-cell development in the thymus was analyzed by flow cytometry. (C and D) Lymphocytes in + − − + − the spleen (C) and lymph nodes (D) were analyzed by flow cytometry. (E)CD4 Tn and Tem cells from Crbn / mice and Crbn / mice were stimulated with anti-CD3 + and anti-CD28 antibodies for the indicated times, after which cell surface expression of CD25 was analyzed by flow cytometry. (F) Proliferation of CD4 Tn and Tem + cells stimulated with anti-CD3 and anti-CD28 antibodies was measured by [3H]thymidine incorporation. (G–J) IL-2 secretion and IL-2 mRNA expression in CD4 Tn and Tem cells stimulated by either anti-CD3 or anti-CD28 antibodies (G and H) or PMA and ionomycin (I and J) were analyzed by ELISA and quantitative RT-PCR. Data are representative of two (A), four (B–D), or three (E–J) independent experiments. Results are expressed as the mean ± SD. *P < 0.05; **P < 0.01, unpaired two-tailed Student’s t test. + − + in Crbn / mice, suggesting that CRBN does not affect the selection ERK and JNK was unaffected in CRBN-deficient CD4 Tn and + of T cells during development (Fig. S2B). However, when CRBN- Tem cells (Fig. 2A). The NF-κB pathway in CD4 T cells also + + deficient CD4 T cells, including CD4 naïve T (Tn) cells and ef- was unaffected, because IκBα degradation (Fig. 2A) and NF-κB − − fector memory T (Tem) cells, from Crbn / mice were stimulated DNA-binding activity (Fig. 2B) were unchanged in CRBN- + + with anti-CD3 and anti-CD28 antibodies, both CD4 Tn and Tem deficient CD4 Tn and Tem cells. However, we found it interesting cells expressed more CD25 on the cell surface compared with the that NF-AT DNA binding (Fig. 2 B and C) and nuclear local- + +/− + control CD4 Tn and Tem cells from their Crbn littermates (Fig. ization (Fig. 2D) in CRBN-deficient CD4 Tn and Tem cells 1E). In contrast to T cells, on B cells a loss of CRBN did not affect were increased after activation, suggesting that loss of CRBN + the activation-induced cell surface expression of CD69 and CD86 in CD4 T cells affects primarily the NF-AT activation signaling C (Fig. S2 ). pathway. Along with the expression of activation markers on the cell + To identify the genes responsible for the increased activation – – + surface, anti-CD3 and anti-CD28 stimulated CD4 Tn and of NF-AT observed in CRBN-deficient CD4 T cells, we ex- Tem cells from CRBN-deficient mice were more proliferative + F + amined gene expression patterns in CD4 Tn cells from CRBN- (Fig.
Load more

Recommended publications
  • Ion Channels 3 1
    r r r Cell Signalling Biology Michael J. Berridge Module 3 Ion Channels 3 1 Module 3 Ion Channels Synopsis Ion channels have two main signalling functions: either they can generate second messengers or they can function as effectors by responding to such messengers. Their role in signal generation is mainly centred on the Ca2 + signalling pathway, which has a large number of Ca2+ entry channels and internal Ca2+ release channels, both of which contribute to the generation of Ca2 + signals. Ion channels are also important effectors in that they mediate the action of different intracellular signalling pathways. There are a large number of K+ channels and many of these function in different + aspects of cell signalling. The voltage-dependent K (KV) channels regulate membrane potential and + excitability. The inward rectifier K (Kir) channel family has a number of important groups of channels + + such as the G protein-gated inward rectifier K (GIRK) channels and the ATP-sensitive K (KATP) + + channels. The two-pore domain K (K2P) channels are responsible for the large background K current. Some of the actions of Ca2 + are carried out by Ca2+-sensitive K+ channels and Ca2+-sensitive Cl − channels. The latter are members of a large group of chloride channels and transporters with multiple functions. There is a large family of ATP-binding cassette (ABC) transporters some of which have a signalling role in that they extrude signalling components from the cell. One of the ABC transporters is the cystic − − fibrosis transmembrane conductance regulator (CFTR) that conducts anions (Cl and HCO3 )and contributes to the osmotic gradient for the parallel flow of water in various transporting epithelia.
    [Show full text]
  • Spatial Distribution of Leading Pacemaker Sites in the Normal, Intact Rat Sinoa
    Supplementary Material Supplementary Figure 1: Spatial distribution of leading pacemaker sites in the normal, intact rat sinoatrial 5 nodes (SAN) plotted along a normalized y-axis between the superior vena cava (SVC) and inferior vena 6 cava (IVC) and a scaled x-axis in millimeters (n = 8). Colors correspond to treatment condition (black: 7 baseline, blue: 100 µM Acetylcholine (ACh), red: 500 nM Isoproterenol (ISO)). 1 Supplementary Figure 2: Spatial distribution of leading pacemaker sites before and after surgical 3 separation of the rat SAN (n = 5). Top: Intact SAN preparations with leading pacemaker sites plotted during 4 baseline conditions. Bottom: Surgically cut SAN preparations with leading pacemaker sites plotted during 5 baseline conditions (black) and exposure to pharmacological stimulation (blue: 100 µM ACh, red: 500 nM 6 ISO). 2 a &DUGLDFIoQChDQQHOV .FQM FOXVWHU &DFQDG &DFQDK *MD &DFQJ .FQLS .FQG .FQK .FQM &DFQDF &DFQE .FQM í $WSD .FQD .FQM í .FQN &DVT 5\U .FQM &DFQJ &DFQDG ,WSU 6FQD &DFQDG .FQQ &DFQDJ &DFQDG .FQD .FQT 6FQD 3OQ 6FQD +FQ *MD ,WSU 6FQE +FQ *MG .FQN .FQQ .FQN .FQD .FQE .FQQ +FQ &DFQDD &DFQE &DOP .FQM .FQD .FQN .FQG .FQN &DOP 6FQD .FQD 6FQE 6FQD 6FQD ,WSU +FQ 6FQD 5\U 6FQD 6FQE 6FQD .FQQ .FQH 6FQD &DFQE 6FQE .FQM FOXVWHU V6$1 L6$1 5$ /$ 3 b &DUGLDFReFHSWRUV $GUDF FOXVWHU $GUDD &DY &KUQE &KUP &KJD 0\O 3GHG &KUQD $GUE $GUDG &KUQE 5JV í 9LS $GUDE 7SP í 5JV 7QQF 3GHE 0\K $GUE *QDL $QN $GUDD $QN $QN &KUP $GUDE $NDS $WSE 5DPS &KUP 0\O &KUQD 6UF &KUQH $GUE &KUQD FOXVWHU V6$1 L6$1 5$ /$ 4 c 1HXURQDOPURWHLQV
    [Show full text]
  • 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.
    [Show full text]
  • Molecular Signatures Differentiate Immune States in Type 1 Diabetes Families
    Page 1 of 65 Diabetes Molecular signatures differentiate immune states in Type 1 diabetes families Yi-Guang Chen1, Susanne M. Cabrera1, Shuang Jia1, Mary L. Kaldunski1, Joanna Kramer1, Sami Cheong2, Rhonda Geoffrey1, Mark F. Roethle1, Jeffrey E. Woodliff3, Carla J. Greenbaum4, Xujing Wang5, and Martin J. Hessner1 1The Max McGee National Research Center for Juvenile Diabetes, Children's Research Institute of Children's Hospital of Wisconsin, and Department of Pediatrics at the Medical College of Wisconsin Milwaukee, WI 53226, USA. 2The Department of Mathematical Sciences, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA. 3Flow Cytometry & Cell Separation Facility, Bindley Bioscience Center, Purdue University, West Lafayette, IN 47907, USA. 4Diabetes Research Program, Benaroya Research Institute, Seattle, WA, 98101, USA. 5Systems Biology Center, the National Heart, Lung, and Blood Institute, the National Institutes of Health, Bethesda, MD 20824, USA. Corresponding author: Martin J. Hessner, Ph.D., The Department of Pediatrics, The Medical College of Wisconsin, Milwaukee, WI 53226, USA Tel: 011-1-414-955-4496; Fax: 011-1-414-955-6663; E-mail: [email protected]. Running title: Innate Inflammation in T1D Families Word count: 3999 Number of Tables: 1 Number of Figures: 7 1 For Peer Review Only Diabetes Publish Ahead of Print, published online April 23, 2014 Diabetes Page 2 of 65 ABSTRACT Mechanisms associated with Type 1 diabetes (T1D) development remain incompletely defined. Employing a sensitive array-based bioassay where patient plasma is used to induce transcriptional responses in healthy leukocytes, we previously reported disease-specific, partially IL-1 dependent, signatures associated with pre and recent onset (RO) T1D relative to unrelated healthy controls (uHC).
    [Show full text]
  • S41598-019-42654-4.Pdf
    www.nature.com/scientificreports OPEN Epigenome-wide Analysis Identifes Genes and Pathways Linked to Neurobehavioral Variation in Received: 22 November 2018 Accepted: 3 April 2019 Preterm Infants Published: xx xx xxxx Todd M. Everson1, Carmen J. Marsit1, T. Michael O’Shea2, Amber Burt 1, Karen Hermetz1, Brian S. Carter3, Jennifer Helderman4, Julie A. Hofeimer2, Elisabeth C. McGowan5, Charles R. Neal6, Steven L. Pastyrnak7, Lynne M. Smith8, Antoine Soliman 9, Sheri A. DellaGrotta10, Lynne M. Dansereau10, James F. Padbury5 & Barry M. Lester5,10,11 Neonatal molecular biomarkers of neurobehavioral responses (measures of brain-behavior relationships), when combined with neurobehavioral performance measures, could lead to better predictions of long-term developmental outcomes. To this end, we examined whether variability in buccal cell DNA methylation (DNAm) associated with neurobehavioral profles in a cohort of infants born less than 30 weeks postmenstrual age (PMA) and participating in the Neonatal Neurobehavior and Outcomes in Very Preterm Infants (NOVI) Study (N = 536). We tested whether epigenetic age, age acceleration, or DNAm levels at individual loci difered between infants based on their NICU Network Neurobehavioral Scale (NNNS) profle classifcations. We adjusted for recruitment site, infant sex, PMA, and tissue heterogeneity. Infants with an optimally well-regulated NNNS profle had older epigenetic age compared to other NOVI infants (β1 = 0.201, p-value = 0.026), but no signifcant diference in age acceleration. In contrast, infants with an atypical NNNS profle had diferential methylation at 29 CpG sites (FDR < 10%). Some of the genes annotated to these CpGs included PLA2G4E, TRIM9, GRIK3, and MACROD2, which have previously been associated with neurological structure and function, or with neurobehavioral disorders.
    [Show full text]
  • 1 1 2 3 Cell Type-Specific Transcriptomics of Hypothalamic
    1 2 3 4 Cell type-specific transcriptomics of hypothalamic energy-sensing neuron responses to 5 weight-loss 6 7 Fredrick E. Henry1,†, Ken Sugino1,†, Adam Tozer2, Tiago Branco2, Scott M. Sternson1,* 8 9 1Janelia Research Campus, Howard Hughes Medical Institute, 19700 Helix Drive, Ashburn, VA 10 20147, USA. 11 2Division of Neurobiology, Medical Research Council Laboratory of Molecular Biology, 12 Cambridge CB2 0QH, UK 13 14 †Co-first author 15 *Correspondence to: [email protected] 16 Phone: 571-209-4103 17 18 Authors have no competing interests 19 1 20 Abstract 21 Molecular and cellular processes in neurons are critical for sensing and responding to energy 22 deficit states, such as during weight-loss. AGRP neurons are a key hypothalamic population 23 that is activated during energy deficit and increases appetite and weight-gain. Cell type-specific 24 transcriptomics can be used to identify pathways that counteract weight-loss, and here we 25 report high-quality gene expression profiles of AGRP neurons from well-fed and food-deprived 26 young adult mice. For comparison, we also analyzed POMC neurons, an intermingled 27 population that suppresses appetite and body weight. We find that AGRP neurons are 28 considerably more sensitive to energy deficit than POMC neurons. Furthermore, we identify cell 29 type-specific pathways involving endoplasmic reticulum-stress, circadian signaling, ion 30 channels, neuropeptides, and receptors. Combined with methods to validate and manipulate 31 these pathways, this resource greatly expands molecular insight into neuronal regulation of 32 body weight, and may be useful for devising therapeutic strategies for obesity and eating 33 disorders.
    [Show full text]
  • KCNA3 Antibody / Kv1.3 (R32012)
    KCNA3 Antibody / Kv1.3 (R32012) Catalog No. Formulation Size R32012 0.5mg/ml if reconstituted with 0.2ml sterile DI water 100 ug Bulk quote request Availability 1-3 business days Species Reactivity Human, Mouse, Rat Format Antigen affinity purified Clonality Polyclonal (rabbit origin) Isotype Rabbit IgG Purity Antigen affinity Buffer Lyophilized from 1X PBS with 2.5% BSA and 0.025% sodium azide UniProt P22001 Applications Western blot : 0.1-0.5ug/ml Limitations This KCNA3 antibody is available for research use only. Western blot testing of 1) rat brain, 2) mouse brain, human 3) K562, 4) HeLa and 5) 22RV1 lysate with KCNA3 antibody. Expected molecular weight ~64 kDa, observed here at ~55 kDa. Description Potassium voltage-gated channel, shaker-related subfamily, member 3, also known as KCNA3 or Kv1.3, is a protein that in humans is encoded by the KCNA3 gene. This gene encodes a member of the potassium channel, voltage-gated, shaker-related subfamily. This member contains six membrane-spanning domains with a shaker-type repeat in the fourth segment. It belongs to the delayed rectifier class, members of which allow nerve cells to efficiently repolarize following an action potential. It plays an essential role in T-cell proliferation and activation. This gene appears to be intronless and it is clustered together with KCNA2 and KCNA10 genes on chromosome 1. And Kv1.3 has been reported to be expressed in the inner mitochondrial membrane in lymphocytes. The apoptotic protein Bax has been suggested to insert into theouter mitochondrial membrane and occlude the pore of Kv1.3 via a lysine residue.
    [Show full text]
  • Graded Co-Expression of Ion Channel, Neurofilament, and Synaptic Genes in Fast- Spiking Vestibular Nucleus Neurons
    Research Articles: Cellular/Molecular Graded co-expression of ion channel, neurofilament, and synaptic genes in fast- spiking vestibular nucleus neurons https://doi.org/10.1523/JNEUROSCI.1500-19.2019 Cite as: J. Neurosci 2019; 10.1523/JNEUROSCI.1500-19.2019 Received: 26 June 2019 Revised: 11 October 2019 Accepted: 25 October 2019 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 © 2019 the authors 1 Graded co-expression of ion channel, neurofilament, and synaptic genes in fast-spiking 2 vestibular nucleus neurons 3 4 Abbreviated title: A fast-spiking gene module 5 6 Takashi Kodama1, 2, 3, Aryn Gittis, 3, 4, 5, Minyoung Shin2, Keith Kelleher2, 3, Kristine Kolkman3, 4, 7 Lauren McElvain3, 4, Minh Lam1, and Sascha du Lac1, 2, 3 8 9 1 Johns Hopkins University School of Medicine, Baltimore MD, 21205 10 2 Howard Hughes Medical Institute, La Jolla, CA, 92037 11 3 Salk Institute for Biological Studies, La Jolla, CA, 92037 12 4 Neurosciences Graduate Program, University of California San Diego, La Jolla, CA, 92037 13 5 Carnegie Mellon University, Pittsburgh, PA, 15213 14 15 Corresponding Authors: 16 Takashi Kodama ([email protected]) 17 Sascha du Lac ([email protected]) 18 Department of Otolaryngology-Head and Neck Surgery 19 The Johns Hopkins University School of Medicine 20 Ross Research Building 420, 720 Rutland Avenue, Baltimore, Maryland, 21205 21 22 23 Conflict of Interest 24 The authors declare no competing financial interests.
    [Show full text]
  • Potassium Channels As Tumour Markers
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector FEBS Letters 580 (2006) 2850–2852 Minireview Potassium channels as tumour markers Walter Stu¨hmera,*, Frauke Alvesb, Franziska Hartunga, Marta Zientkowskab, Luis A. Pardoa a Max-Planck Institute for Experimental Medicine, Hermann-Rein-Strasse 3, 37075 Go¨ttingen, Germany b Department of Hematology and Oncology, University of Go¨ttingen, Robert-Koch-Strasse 40, 37075 Go¨ttingen, Germany Received 1 March 2006; revised 13 March 2006; accepted 22 March 2006 Available online 31 March 2006 Edited by Horst Feldmann iant is permeable to potassium and calcium, as well as being Abstract An increasing number of ion channels are being found to be causally involved in diseases, giving rise to the new field of modulated by cAMP [20]. In addition, extracellular magne- ‘‘channelopathies’’. Cancer is no exception, and several ion chan- sium concentrations are able to modulate the kinetics [21]. nels have been linked to tumour progression. Among them is the The first indications that EAG is involved in the cell cycle potassium channel EAG (Ether-a-go-go). Over 75% of tumours came from the observation that mitosis-promoting factor af- have been tested positive using a monoclonal antibody specific for fects the amount of current through this channel [22] and that EAG, while inhibition of this channel decreased the proliferation the particular cell-cycle stage modulates its selectivity to cae- of EAG expressing cells. The inhibition of EAG is accomplished sium and block by intracellular sodium [23]. Furthermore, using RNA interference, functional anti-EAG1 antibodies, or the microtubule depolymerization that occurs during mitosis (unspecific) EAG channel blockers.
    [Show full text]
  • Potassium Channels and Their Potential Roles in Substance Use Disorders
    International Journal of Molecular Sciences Review Potassium Channels and Their Potential Roles in Substance Use Disorders Michael T. McCoy † , Subramaniam Jayanthi † and Jean Lud Cadet * Molecular Neuropsychiatry Research Branch, NIDA Intramural Research Program, Baltimore, MD 21224, USA; [email protected] (M.T.M.); [email protected] (S.J.) * Correspondence: [email protected]; Tel.: +1-443-740-2656 † Equal contributions (joint first authors). Abstract: Substance use disorders (SUDs) are ubiquitous throughout the world. However, much re- mains to be done to develop pharmacotherapies that are very efficacious because the focus has been mostly on using dopaminergic agents or opioid agonists. Herein we discuss the potential of using potassium channel activators in SUD treatment because evidence has accumulated to support a role of these channels in the effects of rewarding drugs. Potassium channels regulate neuronal action potential via effects on threshold, burst firing, and firing frequency. They are located in brain regions identified as important for the behavioral responses to rewarding drugs. In addition, their ex- pression profiles are influenced by administration of rewarding substances. Genetic studies have also implicated variants in genes that encode potassium channels. Importantly, administration of potassium agonists have been shown to reduce alcohol intake and to augment the behavioral effects of opioid drugs. Potassium channel expression is also increased in animals with reduced intake of methamphetamine. Together, these results support the idea of further investing in studies that focus on elucidating the role of potassium channels as targets for therapeutic interventions against SUDs. Keywords: alcohol; cocaine; methamphetamine; opioids; pharmacotherapy Citation: McCoy, M.T.; Jayanthi, S.; Cadet, J.L.
    [Show full text]
  • Potassium Channel Modulators for the Treatment of Autoimmune Disorders
    Potassium channel modulators for the treatment of autoimmune disorders 1 Autoimmune disorders . During normal immune responses white blood cells protect the body from antigens such as bacteria, viruses, toxins, cancer cells • The cellular immune system attacks infected cells with CD4 (helper) and CD8 (cytotoxic) T cells • The humoral system responds to bacteria and viruses by instigating attack by immunoglobulins produced by B cells . In patients with an autoimmune disorder the immune system cannot distinguish between foreign antigens and healthy tissue, resulting in destruction of tissue or abnormal growth patterns . Many different organ or tissue types may be affected • Blood vessels, connective tissue, nerves, joints, muscles, skin . More than 80 discrete autoimmune disorders have been identified . The aggregate prevalence of AI disorders is ~5000 per 100,000 • Incidence is higher in women than men . Different AI disorders have different molecular phenotypes 2 Autoimmune phenotypes Effector memory T cells and class switched B cells predominate Disease Target organ Autoreactive lymphocyte Psoriasis Skin CD45RO+CD45RA- CCR7- TEM cells Grave disease Thyroid IgD-IgG+ memory B cells Rheumatoid arthritis Joints CD28nullCD45RA-CCR7- TEM cells CD45RA- memory T cells Hashimoto disease Thyroid IgD-IgG+ memory B cells Vitiligo Skin, mucous membranes CD45RO+ memory T cells Crohns disease Digestive tract CD45RO+CD28null memory T cells Type I diabetes CD28 costimulation-independent memory T- Pancreas mellitus cells CD28 costimulation-independent Multiple sclerosis CNS CD45RO+CD45RA-CCR7- TEM cells IgD-CD27+ class-switched memory B cells 3 Prevalence of AI disorders 1600 1400 1200 1000 800 Prevalence of Autoimmune Diseases 600 400 200 (cases/100,000) 0 Psoriasis Grave disease Rheumatoid arthritis Hashimoto's disease Vitiligo IBD Type I diabetes (adults) Pernicious anemia Glomerulonephritis Multiple sclerosis System lupus erythematosis Primary systemic vasculitis Addison Disease .
    [Show full text]
  • Prefrontal Co-Expression of Schizophrenia Risk Genes Is Associated with Treatment Response
    bioRxiv preprint doi: https://doi.org/10.1101/323428; this version posted May 16, 2018. 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 Title: Prefrontal co-expression of schizophrenia risk genes is associated with treatment response 2 in patients 3 4 One Sentence Summary: Schizophrenia risk genes co-expressed in the dorsolateral prefrontal cortex 5 are associated with clinical outcome in patients with schizophrenia. 6 7 Authors: Giulio Pergola1,†, Pasquale Di Carlo1,2,†, Andrew E. Jaffe2,3,4,5, Marco Papalino1, Qiang 8 Chen2, Thomas M. Hyde2,7,8, Joel E. Kleinman2,7, Joo Heon Shin2, Antonio Rampino1,10, Giuseppe 9 Blasi1,10, Daniel R. Weinberger2,6,8,9, Alessandro Bertolino1,10,* 10 11 Affiliations: 12 1Group of Psychiatric Neuroscience, Department of Basic Medical Sciences, Neuroscience and Sense 13 Organs, University of Bari Aldo Moro, Bari, Italy 14 2Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland, 15 USA 16 3Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, 17 Maryland, USA 18 4Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, 19 USA 20 5Center for Computational Biology, Johns Hopkins University, Baltimore, Maryland, USA 21 6Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, Maryland, USA 22 7Department of Neurology, Johns Hopkins School of Medicine, Baltimore, 1 bioRxiv preprint doi: https://doi.org/10.1101/323428; this version posted May 16, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder.
    [Show full text]