DOCSLIB.ORG

The Role of Chloride Channels in Regulation of Pulmonary Artery Smooth Muscle Cell Proliferation

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Role of Chloride Channels in Regulation of Pulmonary Artery Smooth Muscle Cell Proliferation The Role of Chloride Channels in Regulation of Pulmonary Artery Smooth Muscle Cell Proliferation by Wenbin Liang A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Department of Physiology University of Toronto © Copyright by Wenbin Liang, 2011 The Role of Chloride Channels in Regulation of Pulmonary Artery Smooth Muscle Cell Proliferation Wenbin Liang Doctor of Philosophy Department of Physiology University of Toronto 2011 Abstract Pulmonary arterial hypertension (PAH) is a rare but fatal disease with an annual mortality rate of 15% despite current therapies. Uncontrolled proliferation of pulmonary artery smooth muscle cells (PASMCs) results in adverse vascular remodeling contributing to PAH. Understanding the mechanisms of PASMC proliferation may identify new targets for treatment. Chloride currents/channels (ICl) are expressed in PASMCs and their roles in proliferation have been suggested based on their importance in resting membrane potential and cell volume regulation. The present study explored the role of ICl in proliferation in rat and human PASMCs. We found that either nonspecific ICl inhibitors (DIDS or NPPB) or a putative specific blocker of swelling- activated ICl (ICl,swell) reduced proliferation of PASMCs cultured in serum-containing media. Patch-clamp studies showed that proliferating PASMCs had increased baseline ICl and ICl,swell in association with depolarized membrane potentials. Quantitative real-time RT-PCR studies identified expressions of CLC-3, a candidate gene of ICl,swell, and several other CLC genes in proliferating PASMCs. While selective knockdown of CLC-3 with lentiviral shRNA reduced PASMC proliferation, it had no effect on ICl,swell. These findings are consistent with the conclusion that ICl regulate proliferation of PASMCs and suggest that selective ICl inhibition may be useful in treating pulmonary arterial hypertension. ii Acknowledgments It has been a great experience to study in the Ph.D program at the Department of Physiology. The training is a critical part of my life and I am very proud of it. I am indebted to countless people who taught me many things that deeply affect my research and life. My supervisor Dr. Peter Backx is a knowledgeable scientist and inspirational mentor. His enthusiasm in ion channels has a profound influence on this work and my research career. This thesis is dedicated to my co-supervisor Dr. Michael Ward (1956~2009), an eminent scientist and extraordinary mentor, for showing me the joy of doing science. The guidance from my supervisory committee members, Drs. Christine Bear, Steffen-Sebastian Bolz and Scott Heximer, helped me overcoming many hurdles in this work. I would also like to thank my former advisors, Drs. Rui Wang, Lingyun (Lily) Wu and Shizhong Jiang, for introducing me to the exciting field of cardiovascular research. I also thank Dr. Zhong-Ping Feng for help with coursework and Ms. Rosalie Pang, Sandra Monkewich and Dr. Marc Perry for administrative supports. It was my pleasure to know so many great people during my study in the Backx and Ward laboratories. Their knowledge and kindness contributed a lot to my research work. I would like to take this opportunity to thank Drs. B-G. Kerfant, R. A. Rose, R. G. Tsushima, G. Y. Oudit, H. Sun, K-H Kim, N. D'Avanzo, R. Pekhletski, N. Gong, D. Zhao, M. Cieslak, M. M. Patel, M. G. Kabir, M. G. Trivieri, P. C. Papageorgiou, R. D. Vanderlaan, I. Lorenzen-Schmidt, D. Sednev, K. Ban, A. J. Cooper, J. B. Ray, J. Z. He, P. Plant, S. Beca, P. B. Helli, R. Sobbi, J. Simpson, G. P. Farman, J. Liu, Y. Wang, L. Huang, N. Bousette, Y. Fedyshyn, T. Ketela, A. Rosen, M. Mirkhani, B. K. Panama, W. Yang, M. Sellan, and F. Izaddoustdar. I sincerely apologize for those people who helped me but their names are not mentioned here. Finally, I want to thank my family for their encouragements and continuous supports during my study. Without their supports and understanding, I would never finish this work. iii Table of Contents Acknowledgments .......................................................................................................................... iii Table of Contents ........................................................................................................................... iv List of Tables ................................................................................................................................ vii List of Figures .............................................................................................................................. viii List of Appendices .......................................................................................................................... x Chapter 1 General Introduction .................................................................................................... 1 1 Introduction ................................................................................................................................ 2 1.1 Pulmonary Arterial Hypertension (PAH) ........................................................................... 2 1.1.1 PAH: A Disease of Pulmonary Vasculature ........................................................... 2 1.1.2 Hypoxia and PAH ................................................................................................... 4 1.1.3 Phenotypes of Vascular Smooth Muscle Cells ....................................................... 5 1.2 Cellular Proliferation .......................................................................................................... 6 1.2.1 Cell Cycle ................................................................................................................ 6 1.2.2 Cell Volume Regulation and its Role in Proliferation ............................................ 8 1.2.3 Membrane Potential and Ca2+ in Proliferation ...................................................... 10 1.3 Mammalian Cl- Channels .................................................................................................. 11 1.3.1 Cl- Equilibrium and Cl- Channels in Mammalian Tissues .................................... 11 1.3.2 Swelling-Activated Cl- Currents ........................................................................... 13 1.3.3 Ca2+-Activated Cl- Currents .................................................................................. 16 1.3.4 CLC Family .......................................................................................................... 19 1.3.5 Cystic Fibrosis Transmembrane Conductor Regulator (CFTR) ........................... 26 1.3.6 Bestrophin Family ................................................................................................. 27 1.3.7 TMEM16 Family .................................................................................................. 27 1.3.8 Ligand-Gated Cl- Channels ................................................................................... 28 iv 1.4 Aims of Present Studies .................................................................................................... 28 1.5 RNA Interference .............................................................................................................. 29 1.5.1 siRNA-Mediated Gene Silencing ......................................................................... 29 1.5.2 siRNA Duplex Designing ..................................................................................... 31 1.5.3 Validation of Knockdown ..................................................................................... 36 Chapter 2 Materials and Methods .............................................................................................. 38 2 Materials and Methods ............................................................................................................. 39 2.1 Animals ........................................................................................................................... 39 2.2 Detection of PASMC Proliferation by BrdU Uptake In Vivo ......................................... 39 2.3 Acute Dissociation of Rat PASMCs ............................................................................... 39 2.4 Primary Culture of Rat PASMCs ................................................................................... 40 2.5 Effect of Cl- Channel Inhibitors on Cell Number of Cultured Rat PASMCs ................. 40 2.6 Effect of Cl- Channel Inhibitors on BrdU Incorporation and DNA Content in Cultured Rat PASMCs .................................................................................................... 41 2.7 Effect of Cl- Channel Inhibitors on Annexin V and PI Staining in Cultured Rat PASMCs ......................................................................................................................... 41 2.8 Culture and Hypoxia Exposure of Human PASMCs ..................................................... 42 2.9 Immunocytostaining of CLC-3 in Human PASMCs ...................................................... 43 2.10 Quantitative Real-Time Reverse Transcription-PCR (qRT-PCR) ................................. 43 2.11 Lentivirus Generation ..................................................................................................... 44 2.12 Transduction of Human PASMCs .................................................................................. 45 2.13 Recording of Membrane Potential by Whole-Cell Patch-Clamp Technique in Rat PASMCs ........................................................................................................................
Load more

Recommended publications
  • Screening and Identification of Key Biomarkers in Clear Cell Renal Cell Carcinoma Based on Bioinformatics Analysis
    bioRxiv preprint doi: https://doi.org/10.1101/2020.12.21.423889; this version posted December 23, 2020. 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. Screening and identification of key biomarkers in clear cell renal cell carcinoma based on bioinformatics analysis Basavaraj Vastrad1, Chanabasayya Vastrad*2 , Iranna Kotturshetti 1. Department of Biochemistry, Basaveshwar College of Pharmacy, Gadag, Karnataka 582103, India. 2. Biostatistics and Bioinformatics, Chanabasava Nilaya, Bharthinagar, Dharwad 580001, Karanataka, India. 3. Department of Ayurveda, Rajiv Gandhi Education Society`s Ayurvedic Medical College, Ron, Karnataka 562209, India. * Chanabasayya Vastrad [email protected] Ph: +919480073398 Chanabasava Nilaya, Bharthinagar, Dharwad 580001 , Karanataka, India bioRxiv preprint doi: https://doi.org/10.1101/2020.12.21.423889; this version posted December 23, 2020. 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. Abstract Clear cell renal cell carcinoma (ccRCC) is one of the most common types of malignancy of the urinary system. The pathogenesis and effective diagnosis of ccRCC have become popular topics for research in the previous decade. In the current study, an integrated bioinformatics analysis was performed to identify core genes associated in ccRCC. An expression dataset (GSE105261) was downloaded from the Gene Expression Omnibus database, and included 26 ccRCC and 9 normal kideny samples. Assessment of the microarray dataset led to the recognition of differentially expressed genes (DEGs), which was subsequently used for pathway and gene ontology (GO) enrichment analysis.
    [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]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • Control Qpatch Htx Multi-Hole
    41577_Poster 170x110.qxd:Poster 170x110 07/04/10 8:52 Side 1 SOPHION BIOSCIENCE A/S SOPHION BIOSCIENCE, INC. SOPHION JAPAN Baltorpvej 154 675 US Highway One 1716-6, Shimmachi ENHANCING THROUGHPUT WITH MULTIPLE DK-2750 Ballerup North Brunswick, NJ 08902 Takasaki-shi, Gumma 370-1301 DENMARK USA JAPAN [email protected] Phone: +1 732 745 0221 Phone: +81 274 50 8388 CELL LINES PER WELL WITH THE QPATCH HTX www.sophion.com www.sophion.com www.sophion.com HERVØR LYKKE OLSEN l DORTHE NIELSEN l MORTEN SUNESEN QPATCH HTX MULTI-HOLE: TEMPORAL CURRENT QPATCH HTX MULTI-HOLE: PHARMACOLOGICAL SEPARATION BASED ON DISCRETE RECORDING SEPARATION BASED ON ION CHANNEL INHIBITORS TIME WINDOWS KvLQT1/minK (KCNQ1/KCNE1) INTRODUCTION Kv1.5 (KCNA5) ABRaw traces (A) and Hill plot (B) for XE991. ABC hERG and Nav1.5 blocked by E-4031 and The QPatch HTX automated patch clamp technology was developed to 1) increase throughput in ion channel drug TTX, respectively. screening by parallel operation of 48 multi-hole patch clamp sites, each comprising 10 individual patch clamp holes, in a single measurements site on a QPlate X, and 2) diminish problems with low-expressing cell lines. Thus, parallel recording from 10 cells represents a 10-fold signal amplification, and it increases the success rate at each site substantially. To further increase throughput we explored the possibility of simultaneous recording of a number of ion channel currents. IC50 (μM) XE991 Two or three cell lines, each expressing a specific ion channel, were applied at each site simultaneously. The ion channel Measured Literature currents were separated temporally or pharmacologically by proper choices of voltage protocols or ion channel KvLQT1 3.5±1.0 (n=12) 1-6 (Ref.
    [Show full text]
  • Inherited Renal Tubulopathies—Challenges and Controversies
    G C A T T A C G G C A T genes Review Inherited Renal Tubulopathies—Challenges and Controversies Daniela Iancu 1,* and Emma Ashton 2 1 UCL-Centre for Nephrology, Royal Free Campus, University College London, Rowland Hill Street, London NW3 2PF, UK 2 Rare & Inherited Disease Laboratory, London North Genomic Laboratory Hub, Great Ormond Street Hospital for Children National Health Service Foundation Trust, Levels 4-6 Barclay House 37, Queen Square, London WC1N 3BH, UK; [email protected] * Correspondence: [email protected]; Tel.: +44-2381204172; Fax: +44-020-74726476 Received: 11 February 2020; Accepted: 29 February 2020; Published: 5 March 2020 Abstract: Electrolyte homeostasis is maintained by the kidney through a complex transport function mostly performed by specialized proteins distributed along the renal tubules. Pathogenic variants in the genes encoding these proteins impair this function and have consequences on the whole organism. Establishing a genetic diagnosis in patients with renal tubular dysfunction is a challenging task given the genetic and phenotypic heterogeneity, functional characteristics of the genes involved and the number of yet unknown causes. Part of these difficulties can be overcome by gathering large patient cohorts and applying high-throughput sequencing techniques combined with experimental work to prove functional impact. This approach has led to the identification of a number of genes but also generated controversies about proper interpretation of variants. In this article, we will highlight these challenges and controversies. Keywords: inherited tubulopathies; next generation sequencing; genetic heterogeneity; variant classification. 1. Introduction Mutations in genes that encode transporter proteins in the renal tubule alter kidney capacity to maintain homeostasis and cause diseases recognized under the generic name of inherited tubulopathies.
    [Show full text]
  • The Chondrocyte Channelome: a Novel Ion Channel Candidate in the Pathogenesis of Pectus Deformities
    Old Dominion University ODU Digital Commons Biological Sciences Theses & Dissertations Biological Sciences Summer 2017 The Chondrocyte Channelome: A Novel Ion Channel Candidate in the Pathogenesis of Pectus Deformities Anthony J. Asmar Old Dominion University, [email protected] Follow this and additional works at: https://digitalcommons.odu.edu/biology_etds Part of the Biology Commons, Molecular Biology Commons, and the Physiology Commons Recommended Citation Asmar, Anthony J.. "The Chondrocyte Channelome: A Novel Ion Channel Candidate in the Pathogenesis of Pectus Deformities" (2017). Doctor of Philosophy (PhD), Dissertation, Biological Sciences, Old Dominion University, DOI: 10.25777/pyha-7838 https://digitalcommons.odu.edu/biology_etds/19 This Dissertation is brought to you for free and open access by the Biological Sciences at ODU Digital Commons. It has been accepted for inclusion in Biological Sciences Theses & Dissertations by an authorized administrator of ODU Digital Commons. For more information, please contact [email protected]. THE CHONDROCYTE CHANNELOME: A NOVEL ION CHANNEL CANDIDATE IN THE PATHOGENESIS OF PECTUS DEFORMITIES by Anthony J. Asmar B.S. Biology May 2010, Virginia Polytechnic Institute M.S. Biology May 2013, Old Dominion University A Dissertation Submitted to the Faculty of Old Dominion University in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY BIOMEDICAL SCIENCES OLD DOMINION UNIVERSITY August 2017 Approved by: Christopher Osgood (Co-Director) Michael Stacey (Co-Director) Lesley Greene (Member) Andrei Pakhomov (Member) Jing He (Member) ABSTRACT THE CHONDROCYTE CHANNELOME: A NOVEL ION CHANNEL CANDIDATE IN THE PATHOGENESIS OF PECTUS DEFORMITIES Anthony J. Asmar Old Dominion University, 2017 Co-Directors: Dr. Christopher Osgood Dr. Michael Stacey Costal cartilage is a type of rod-like hyaline cartilage connecting the ribs to the sternum.
    [Show full text]
  • 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
    [Show full text]
  • Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
    [Show full text]
  • An Advance About the Genetic Causes of Epilepsy
    E3S Web of Conferences 271, 03068 (2021) https://doi.org/10.1051/e3sconf/202127103068 ICEPE 2021 An advance about the genetic causes of epilepsy Yu Sun1, a, *, †, Licheng Lu2, b, *, †, Lanxin Li3, c, *, †, Jingbo Wang4, d, *, † 1The School of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801-3633, US 2High School Affiliated to Shanghai Jiao Tong University, Shanghai, 200441, China 3Applied Biology program, University of British Columbia, Vancouver, V6r3b1, Canada 4School of Chemical Machinery and Safety, Dalian University of Technology, Dalian, 116023, China †These authors contributed equally. Abstract: Human hereditary epilepsy has been found related to ion channel mutations in voltage-gated channels (Na+, K+, Ca2+, Cl-), ligand gated channels (GABA receptors), and G-protein coupled receptors, such as Mass1. In addition, some transmembrane proteins or receptor genes, including PRRT2 and nAChR, and glucose transporter genes, such as GLUT1 and SLC2A1, are also about the onset of epilepsy. The discovery of these genetic defects has contributed greatly to our understanding of the pathology of epilepsy. This review focuses on introducing and summarizing epilepsy-associated genes and related findings in recent decades, pointing out related mutant genes that need to be further studied in the future. 1 Introduction Epilepsy is a neurological disorder characterized by 2 Malfunction of Ion channel epileptic seizures caused by abnormal brain activity. 1 in Functional variation in voltage or ligand-gated ion 100 (50 million people) people are affected by symptoms channel mutations is a major cause of idiopathic epilepsy, of this disorder worldwide, with men, young children, and especially in rare genetic forms.
    [Show full text]
  • Inhibition of Radiation and Temozolomide-Induced Glioblastoma Invadopodia Activity Using Ion Channel Drugs
    cancers Article Inhibition of Radiation and Temozolomide-Induced Glioblastoma Invadopodia Activity Using Ion Channel Drugs Marija Dinevska 1 , Natalia Gazibegovic 2 , Andrew P. Morokoff 1,3, Andrew H. Kaye 1,4, Katharine J. Drummond 1,3, Theo Mantamadiotis 1,5 and Stanley S. Stylli 1,3,* 1 Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Parkville 3050, Victoria, Australia; [email protected] (M.D.); morokoff@unimelb.edu.au (A.P.M.); [email protected] (A.H.K.); [email protected] (K.J.D.); [email protected] (T.M.) 2 Victoria University, St. Albans 3021, Victoria, Australia; [email protected] 3 Department of Neurosurgery, The Royal Melbourne Hospital, Parkville 3050, Victoria, Australia 4 Hadassah University Medical Centre, Jerusalem 91120, Israel 5 Department of Microbiology & Immunology, School of Biomedical Sciences, The University of Melbourne, Parkville 3010, Victoria, Australia * Correspondence: [email protected] or [email protected] Received: 8 September 2020; Accepted: 30 September 2020; Published: 8 October 2020 Simple Summary: Glioblastoma accounts for approximately 40–50% of all primary brain cancers and is a highly aggressive cancer that rapidly disseminates within the surrounding normal brain. Dynamic actin-rich protrusions known as invadopodia facilitate this invasive process. Ion channels have also been linked to a pro-invasive phenotype and may contribute to facilitating invadopodia activity in cancer cells. The aim of our study was to screen ion channel-targeting drugs for their cytotoxic efficacy and potential anti-invadopodia properties in glioblastoma cells. We demonstrated that the targeting of ion channels in glioblastoma cells can lead to a reduction in invadopodia activity and protease secretion.
    [Show full text]
  • Cldn19 Clic2 Clmp Cln3
    NewbornDx™ Advanced Sequencing Evaluation When time to diagnosis matters, the NewbornDx™ Advanced Sequencing Evaluation from Athena Diagnostics delivers rapid, 5- to 7-day results on a targeted 1,722-genes. A2ML1 ALAD ATM CAV1 CLDN19 CTNS DOCK7 ETFB FOXC2 GLUL HOXC13 JAK3 AAAS ALAS2 ATP1A2 CBL CLIC2 CTRC DOCK8 ETFDH FOXE1 GLYCTK HOXD13 JUP AARS2 ALDH18A1 ATP1A3 CBS CLMP CTSA DOK7 ETHE1 FOXE3 GM2A HPD KANK1 AASS ALDH1A2 ATP2B3 CC2D2A CLN3 CTSD DOLK EVC FOXF1 GMPPA HPGD K ANSL1 ABAT ALDH3A2 ATP5A1 CCDC103 CLN5 CTSK DPAGT1 EVC2 FOXG1 GMPPB HPRT1 KAT6B ABCA12 ALDH4A1 ATP5E CCDC114 CLN6 CUBN DPM1 EXOC4 FOXH1 GNA11 HPSE2 KCNA2 ABCA3 ALDH5A1 ATP6AP2 CCDC151 CLN8 CUL4B DPM2 EXOSC3 FOXI1 GNAI3 HRAS KCNB1 ABCA4 ALDH7A1 ATP6V0A2 CCDC22 CLP1 CUL7 DPM3 EXPH5 FOXL2 GNAO1 HSD17B10 KCND2 ABCB11 ALDOA ATP6V1B1 CCDC39 CLPB CXCR4 DPP6 EYA1 FOXP1 GNAS HSD17B4 KCNE1 ABCB4 ALDOB ATP7A CCDC40 CLPP CYB5R3 DPYD EZH2 FOXP2 GNE HSD3B2 KCNE2 ABCB6 ALG1 ATP8A2 CCDC65 CNNM2 CYC1 DPYS F10 FOXP3 GNMT HSD3B7 KCNH2 ABCB7 ALG11 ATP8B1 CCDC78 CNTN1 CYP11B1 DRC1 F11 FOXRED1 GNPAT HSPD1 KCNH5 ABCC2 ALG12 ATPAF2 CCDC8 CNTNAP1 CYP11B2 DSC2 F13A1 FRAS1 GNPTAB HSPG2 KCNJ10 ABCC8 ALG13 ATR CCDC88C CNTNAP2 CYP17A1 DSG1 F13B FREM1 GNPTG HUWE1 KCNJ11 ABCC9 ALG14 ATRX CCND2 COA5 CYP1B1 DSP F2 FREM2 GNS HYDIN KCNJ13 ABCD3 ALG2 AUH CCNO COG1 CYP24A1 DST F5 FRMD7 GORAB HYLS1 KCNJ2 ABCD4 ALG3 B3GALNT2 CCS COG4 CYP26C1 DSTYK F7 FTCD GP1BA IBA57 KCNJ5 ABHD5 ALG6 B3GAT3 CCT5 COG5 CYP27A1 DTNA F8 FTO GP1BB ICK KCNJ8 ACAD8 ALG8 B3GLCT CD151 COG6 CYP27B1 DUOX2 F9 FUCA1 GP6 ICOS KCNK3 ACAD9 ALG9
    [Show full text]