DOCSLIB.ORG

Update on the Implication of Potassium Channels in Autism: K+ Channelautism Spectrum Disorder

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Update on the Implication of Potassium Channels in Autism: K+ Channelautism Spectrum Disorder REVIEW ARTICLE published: 02 March 2015 doi: 10.3389/fncel.2015.00034 Update on the implication of potassium channels in autism: K+ channelautism spectrum disorder Luca Guglielmi 1*, Ilenio Servettini 1, Martino Caramia 2 , Luigi Catacuzzeno 2 , Fabio Franciolini 2 , Maria Cristina D’Adamo1 and Mauro Pessia1* 1 Section of Physiology and Biochemistry, Department of Experimental Medicine, University of Perugia School of Medicine, Perugia, Italy 2 Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy Edited by: Autism spectrum disorders (ASDs) are characterized by impaired ability to properly Tycho M. Hoogland, Netherlands implement environmental stimuli that are essential to achieve a state of social and Institute for Neuroscience, Netherlands cultural exchange. Indeed, the main features of ASD are impairments of interpersonal relationships, verbal and non-verbal communication and restricted and repetitive behaviors. Reviewed by: Noritaka Ichinohe, National Institute of These aspects are often accompanied by several comorbidities such as motor delay, Neuroscience – National Center of praxis impairment, gait abnormalities, insomnia, and above all epilepsy. Genetic analyses Neurology and Psychiatry, Japan of autistic individuals uncovered deleterious mutations in several K+ channel types Mohamed Jaber, University of Poitiers, France strengthening the notion that their intrinsic dysfunction may play a central etiologic role in ASD. However, indirect implication of K+ channels in ASD has been also reported. *Correspondence: + Luca Guglielmi and Mauro Pessia, For instance, loss of fragile X mental retardation protein (FMRP) results in K channels Section of Physiology and deregulation, network dysfunction and ASD-like cognitive and behavioral symptoms. This Biochemistry, Department of review provides an update on direct and indirect implications of K+ channels in ASDs. Experimental Medicine, University of Perugia School of Medicine, Owing to a mounting body of evidence associating a channelopathy pathogenesis to P.leGambuli, Edificio D-Piano 1, autism and showing that nearly 500 ion channel proteins are encoded by the human 06132 San Sisto, Perugia, Italy genome, we propose to classify ASDs - whose susceptibility is significantly enhanced e-mail: [email protected]; by ion channels defects, either in a monogenic or multigenic condition - in a new category [email protected] named “channelAutism Spectrum Disorder”(channelASD; cASD) and introduce a new taxonomy (e.g., Kvx.y-channelASD and likewise Navx.y-channelASD,Cavx.y-channelASD; etc.). This review also highlights some degree of clinical and genetic overlap between K+ channelASDs and K+ channelepsies, whereby such correlation suggests that a subcategory characterized by a channelASD-channelepsy phenotype may be distinguished. Ultimately, this overview aims to further understand the different clinical subgroups and help parse out the distinct biological basis of autism that are essential to establish patient-tailored treatments. + Keywords: K channels, Kv4.2 (KCND2), Kv7.3(KCNQ3), KCa1.1 (KCNMA1), Kir2.1 (KCNJ2), Kir4.1 (KCNJ10), FMRP (FMR1), channelASD-channelepsy phenotype INTRODUCTION severity of the symptoms, ASD is thought to be caused by mul- Nearly 70 million people worldwide suffer from ASD. 700,000 are tiple factors interacting in a complex way. Genetic defects, both from USA and the estimated cost to society of caring for these chil- inherited or occurring spontaneously, undoubtedly play a role dren has been $11.5 billion in 2011 (Lavelle et al., 2014). ASD is a in increasing the susceptibility to the disorder by affecting brain group of heterogeneous neurodevelopmental disorders previously development and proper neural networking. Neurological comor- dealt with as single pathologies: autistic disorder, pervasive devel- bidities are often observed in ASD patients and they are associated opmental disorder-not otherwise specified (PDD-NOS), Asperger with more clinical severity. The most noted is epilepsy, comor- syndrome, childhood disintegrative disorder also known as Heller bid in 30% of ASD, about 50 times higher than in the general syndrome, and Rett syndrome. Specific impairments before age population (Tuchman and Rapin, 2002; Mouridsen et al., 2011). three, in each of the following three core domains fit the diagnos- Cognitive and behavioral deficits occurs in up to 46% of children tic criteria for ASD: social (difficulty in interacting with people, with epilepsy (Clarke et al., 2005; Matsuo et al., 2010) suggesting in reading facial expressions and making eye contact), language that, at least in these cases, the excitability imbalance could be a (difficulty in using or understanding language, tending to focus common denominator. Another comorbidity observed in nearly attention and conversation on a limited number of topics, fre- 90% of genetic syndromes associated with ASDs is motor delay. quently repeat phrases, and have very limited speech ability), and Delays occur in both gross and fine motor domains, while deficits restricted/repetitive behavior (excessive attention to routines and are documented in praxis, motor planning, gait, coordination, and difficulty in adjusting to new surroundings or changes in rou- postural control (Rinehart and McGinley, 2010; Van Waelvelde tine). Given the complexity of the disorder and the variety and et al., 2010). Several lines of evidence suggest that motor delay is Frontiers in Cellular Neuroscience www.frontiersin.org March 2015 | Volume 9 | Article 34 | 1 Guglielmi et al. K+ Channelautism caused by aberrant neural circuitry mostly in the cerebellum and as homomers, whenever four identical α-subunits are assem- fronto-striatal regions (Rinehart et al., 2006; Wegiel et al., 2013). bled or as heteromers, whenever different types of α-subunits The relative risk for a child to develop the disease is increased heteropolymerize to form channels with distinct functional and ∼25-fold in families in which a sibling is affected (Jorde et al., pharmacological properties (Pessia, 2004). 1991). Unfortunately, the genetic etiology of autism is character- ized by high locus heterogeneity, where de novo and rare inherited Kv4.2 – ChannelASD CNVs and SNV mutations in conjunction contribute to the over- KCND2 gene encodes for the α subunit of the voltage-gated K+ all genetic risk to develop the disease. To date, we know that channel Kv4.2 that generates an “A-type” current (IA). When defined mutations, genetic syndromes and de novo CNVs account assembled in homotetramers, Kv4.2 channels activate at sub- for about 30% of ASD cases (Schaaf and Zoghbi, 2011). Link- threshold membrane potentials, inactivate rapidly, and quickly age analyses of ASD patients have allowed the identification of recover from inactivation (Zhu et al., 1999; Birnbaum et al., 2004). loss- or gain-of-function mutations and chromosomal alterations The availability of this channel type, in response to membrane in genes coding for several channel types, including K+ chan- potential fluctuation, is regulated by its peculiar inactivation nels. These proteins are highly heterogenic and widely expressed kinetics occurring from the open state by a fast N-type mech- in the CNS where they set the resting membrane potential of anism or (much more frequently) from pre-open closed states, neurons and glia, shape action potentials and regulate firing, when the voltage-sensor domains activate but the pore fails to neurotransmitter release and wiring. At network level, K+ chan- open (Bahring et al., 2001; Gebauer et al., 2004; Jerng et al., nels are involved in post-synaptic EPSP-spike coupling, activity 2004; Barghaan and Bahring, 2009; Bahring and Covarrubias, dependent short- and long-term synaptic plasticity and informa- 2011). In vivo, other proteins further tune-up Kv4.2 inactiva- tion processing. Thus, these channels provide neurons, glia and tion kinetics: the K+ channel interacting protein (KChIP) and the CNS networks with distinct electrical identity and their dysfunc- dipeptidyl-peptidase-like protein (DPP) that respectively inhibits tion is a major contributing factor in excitability disequilibrium and accentuates N-type open state inactivation (Wang et al., 2002; and network impairment. Animal models, in which these genes Jerng et al., 2005, 2009; Covarrubias et al., 2008). This channel type are deleted or mutated, often show epilepsy (Eijkelkamp et al., is mainly expressed in the hippocampal CA1 pyramidal neurons 2012; D’Adamo et al., 2013, 2014), motor impairment, learn- where it regulates the threshold for action potential initiation and ing and behavioral phenotypes that resemble somehow ASD. repolarization, frequency-dependent AP broadening, and back- The insights, provided by investigations with these animal mod- propagation of action potentials (Chen et al., 2006; Kim et al., els, are valuable to understand neural networks abnormalities 2007; Nerbonne et al., 2008). These notions were further corrob- potentially underlying ASD. The plethora of ion channel types orated by the evidence that Kv4.2 channel deletion lowers and expressed by neurons and the numerous variations discovered increases the threshold for LTP and LTD induction, respectively in their relevant genes often generate confusion in the classi- (Chen et al., 2006; Zhao et al., 2011). Conversely, enhancement fication of the associated diseases. To further understand the of Kv4.2 expression prevents LTP induction (Jung et al., 2008). clinical subgroups of autism, help parse out distinct
Load more

Recommended publications
  • 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]
  • 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]
  • 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]
  • Supplemental Text and Figures
    Supplemental Materials and Methods Experimental bone metastasis assay Primary PCa cells were sorted by GFP marker from mTmG+ tumors, and 105 cells in 20μL PBS were injected using Hamilton syringe into the tibia of 6-week old NSG mice. Mice were monitored biweekly for moribund signs for euthanasia and organ harvest. Noninvasive mouse and ex vivo imaging MRI imaging with Bruker ICON and fluorescence imaging of fresh organs with metastasis enumeration were recently described (Lu et al. 2017). Primary prostate cell sphere formation assay Isolate of primary cells from prostate, culture and counting of prostatospheres on Matrigel were performed as described (Lukacs et al. 2010). For organoid culture assay, we followed a published matrigel embedding method (Chua et al. 2014). RNA-Seq and differential gene expression Total RNA was isolated from prostate tumors using Direct-zol RNA MiniPrep Kit (Zymo Research) and processed for stranded total RNA-Seq using Illumina HiSeq 4000 at Sequencing and Microarray Facility at MD Anderson Cancer Center. The differential expression analysis was performed using the DESeq2 package of R. P-values obtained after multiple binomial tests were adjusted using BH method. Significant genes are defined by using a cut-off of 0.05 on the BH corrected p-value and an absolute log2 fold change value of at least 1.5. Histology and western blot H&E stain, immunohistochemical (IHC) and western blot were performed as previously described (Ding et al. 2011; Wang et al. 2016). Primary antibodies for IHC include Ki67 (Fisher, RM-9106-S1), cleaved caspase 3 (Cell Signaling Technology aka CST, 9661), cyclin D1 (Fisher, clone SP4), TGFBR2 (Abcam, ab61213), BMPR2 (Abcam, ab130206), AR (EMD Millipore, 06-680), phospho- Akt (CST, 4060), GFP (CST, 2956), E-Cadherin (CST, 14472).
    [Show full text]
  • Dimethylation of Histone 3 Lysine 9 Is Sensitive to the Epileptic Activity
    1368 MOLECULAR MEDICINE REPORTS 17: 1368-1374, 2018 Dimethylation of Histone 3 Lysine 9 is sensitive to the epileptic activity, and affects the transcriptional regulation of the potassium channel Kcnj10 gene in epileptic rats SHAO-PING ZHANG1,2*, MAN ZHANG1*, HONG TAO1, YAN LUO1, TAO HE3, CHUN-HUI WANG3, XIAO-CHENG LI3, LING CHEN1,3, LIN-NA ZHANG1, TAO SUN2 and QI-KUAN HU1-3 1Department of Physiology; 2Ningxia Key Laboratory of Cerebrocranial Diseases, Incubation Base of National Key Laboratory, Ningxia Medical University; 3General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China Received February 18, 2017; Accepted September 13, 2017 DOI: 10.3892/mmr.2017.7942 Abstract. Potassium channels can be affected by epileptic G9a by 2-(Hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-6,7-di- seizures and serve a crucial role in the pathophysiology of methoxy-N-(1-(phenyl-methyl)-4-piperidinyl)-4-quinazolinamine epilepsy. Dimethylation of histone 3 lysine 9 (H3K9me2) and tri-hydrochloride hydrate (bix01294) resulted in upregulation its enzyme euchromatic histone-lysine N-methyltransferase 2 of the expression of Kir4.1 proteins. The present study demon- (G9a) are the major epigenetic modulators and are associated strated that H3K9me2 and G9a are sensitive to epileptic seizure with gene silencing. Insight into whether H3K9me2 and G9a activity during the acute phase of epilepsy and can affect the can respond to epileptic seizures and regulate expression of transcriptional regulation of the Kcnj10 channel. genes encoding potassium channels is the main purpose of the present study. A total of 16 subtypes of potassium channel Introduction genes in pilocarpine-modelled epileptic rats were screened by reverse transcription-quantitative polymerase chain reac- Epilepsies are disorders of neuronal excitability, characterized tion, and it was determined that the expression ATP-sensitive by spontaneous and recurrent seizures.
    [Show full text]
  • Gene List of the Targeted NGS MCD and CCA Gene Panel AKT3,ALX1
    Gene List of the targeted NGS MCD and CCA gene panel AKT3,ALX1,ALX3,ALX4,AMPD2,ARFGEF2,ARID1B,ARX,ASPM,ATR,ATRX,B3GALTL,BRPF1,c12orf57,C6orf70,CASK,CCND2,CDK5RAP2,CDON,C ENPJ,CEP170,CHMP1A,COL4A1,CREBBP,CYP11A1,DCHS1,DCLK1,DCX,DHCR24,DHCR7,DIS3L2,DISC1,DISP1,DLL1,DMRTA2,DYNC1H1,DYRK1 A,EARS2,EFNB1,EMX1,EOMES,EP300,ERBB4,ERMARD,EXOSC3,FAM36A,FGF8,FGFR1,FGFR2,FLNA,FOXC1,FOXG1,FOXH1,FZD10,GLI2,GLI3,GP R56,GPSM2,HCCS,HESX1,HNRNPU,IGBP1,IGFBP1,ISPD,ITPA,KAL1,KAT6B,KATNB1,KIAA1279,KIF14,KIF1A,KIF1B,KIF21A,KIF2A,KIF5C,KIF7,L1 CAM,LAMB1,LAMC3,LRP2,MCPH1,MED12,MID1,NDE1,NFIB,NPC1,NR2F1,NSD1,NTRK1,NTRK3,OCEL1,OPA1,OTX2,PAFAH1B1,PAX6,PEX1,PHF1 0,PIK3R2,POLR3A,POLR3B,POMT1,POMT2,PTCH1,PTPRS,PYCR1,RAB3GAP1,RARS2,RELN,RFX3,ROBO1,ROBO3,RPS6KA3,RTTN,SATB2,SEPSEC S,SHH,SIX3,SLC12A6,SOX2,SPOCK1,SRPX2,TBCD,TBCE,TCF4,TDGF1,TEAD1,THBS2,TMEM5,TSC1,TSC2,TSEN15,TSEN2,TSEN34,TSEN54,TUBA1 A,TUBA8,TUBB,TUBB2A,TUBB2B,TUBB3,TUBB4A,TUBG1,VAX1,VRK1,WDR47,WDR62,ZBTB18,ZEB2,ZIC2. Gene List of the targeted NGS epilepsy gene panel AARS, ADGRV1, ADRA2B, ADSL, ALDH4A1, ALDH7A1, ALG13, ALPL, ARHGEF15, ARHGEF9, ARX, ASAH1, ATP1A2, ATP1A3, BRD2, CACNA1A, CACNA1H, CACNA2D2, CACNB4, CBL, CDKL5, CERS1, CHD2, CHRNA2, CHRNA4, CHRNB2, CLCN2, CLCN4, CLN8, CLTC, CNKSR2, CNTNAP2, CPA6, CPLX1, CSNK1G1, CSNK2B, CTNND2, DEPDC5, DHDDS, DNM1, DOCK7, DYNC1H1, EEF1A2, EFHC1, EIF2S3, EMC1, EPM2A, FASN, FLNA, FOXG1, GABBR2, GABRA1, GABRA2, GABRA3, GABRB2, GABRB3, GABRD, GABRG2, GAL, GNAO1, GOSR2, GRIA1, GRIN1, GRIN2A, GRIN2B, HCN1, HCN4, HDAC4, HNRNPU, IDH3A, IQSEC2, JRK, KCNA1, KCNA2, KCNB1,
    [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]
  • Mutations of Voltage-Gated Ionic Channels and Risk of Severe Cardiac Arrhythmias
    Acta Cardiol Sin 2019;35:99-110 Review Article doi: 10.6515/ACS.201903_35(2).20181028A Mutations of Voltage-Gated Ionic Channels and Risk of Severe Cardiac Arrhythmias Amir Dehghani-Samani,1 Samin Madreseh-Ghahfarokhi2 and Azam Dehghani-Samani3 Background: Arrhythmias as important malfunctions of heart are known as abnormal rhythm of heart. Several causes can make arrhythmias and most of them are related to generation and/or conduction of action potential in heart. Action potential in myocytes results from the sequential opening and closing of ion channel proteins that span the plasma membrane of individual myocytes. Action potential’s conduction through the heart is depended on electrical coupling between myocytes, which is mediated by gap junctions. Generation and conduction of action potentials are related to perfect action of ionic channels in heart. Objectives: This novel review comprehensively addressed the ionic mechanisms of the arrhythmogenic mutations in cardiac voltage-gated ionic channels including: CACNA1C, CACNA1D, KCNA5, KCND2, KCND3, KCNE1, KCNE2, KCNE5, KCNH2, KCNJ2, KCNJ5, KCNQ1, SCN4A, SCN5A, SCN1B, SCN2B, SCN3B and SCN4B. Methods: Current study, for the first time, review and discuses about relation between cardiac arrhythmias and whole of important voltage gated ionic channels from different families, altogether and at the same time. Results: This review clears that mutations in voltage-gated ionic channels play important roles in generation of severe cardiac arrhythmias, and among them it is looked that mutations in voltage-gated potassium channels are more important. Conclusions: Most of induced arrhythmias due to voltage-gated ionic channels mutations result in action potentials prolongation and long QT syndromes.
    [Show full text]
  • The Effects of Artificially Dosed Adult Rumen Contents on Abomasum
    G C A T T A C G G C A T genes Article The Effects of Artificially Dosed Adult Rumen Contents on Abomasum Transcriptome and Associated Microbial Community Structure in Calves Naren Gaowa 1 , Wenli Li 2,*, Brianna Murphy 2 and Madison S. Cox 3,4 1 State Key Laboratory of Animal Nutrition, Beijing Engineering Technology, Research Center of Raw Milk Quality and Safety Control, College of Animal Science and Technology, China Agricultural University, No.2 Yuanmingyuan West Road, Haidian, Beijing 100193, China; [email protected] 2 The Cell Wall Utilization and Biology Laboratory, USDA Agricultural Research Service, US Dairy Forage Research Center, Madison, WI 53706, USA; [email protected] 3 Department of Bacteriology, University of Wisconsin-Madison, Madison, WI 53706, USA; [email protected] 4 Microbiology Doctoral Training Program, University of Wisconsin-Madison, Madison, WI 53706, USA * Correspondence: [email protected]; Tel.: +1-(608)-890-0056 Abstract: This study aimed to investigate the changes in abomasum transcriptome and the associated microbial community structure in young calves with artificially dosed, adult rumen contents. Eight young bull calves were randomly dosed with freshly extracted rumen contents from an adult cow (high efficiency (HE), n = 4), or sterilized rumen content (Con, n = 4). The dosing was administered within 3 days of birth, then at 2, 4, and 6 weeks following the initial dosing. Abomasum tissues were collected immediately after sacrifice at 8 weeks of age. Five genera (Tannerella, Desulfovibrio, Deinococcus, Leptotrichia, and Eubacterium; p < 0.05) showed significant difference in abundance Citation: Gaowa, N.; Li, W.; Murphy, between the treatments.
    [Show full text]
  • Redalyc.Hormonal Control of Cardiac Action Potential Phase 1 Currents in the Brugada Syndrome
    Revista Argentina de Cardiología ISSN: 0034-7000 [email protected] Sociedad Argentina de Cardiología Argentina ARGENZIANO, MARIANA; TISCORNIA, GISELA; MORETTA, ROSALIA; AMORENA, CARLOS E.; GARCIA GRAS, EDUARDO Hormonal Control of Cardiac Action Potential Phase 1 Currents in the Brugada Syndrome Revista Argentina de Cardiología, vol. 82, núm. 4, agosto, 2014, pp. 292-297 Sociedad Argentina de Cardiología Buenos Aires, Argentina Available in: http://www.redalyc.org/articulo.oa?id=305331882005 How to cite Complete issue Scientific Information System More information about this article Network of Scientific Journals from Latin America, the Caribbean, Spain and Portugal Journal's homepage in redalyc.org Non-profit academic project, developed under the open access initiative ORIGINAL ARTICLE Hormonal Control of Cardiac Action Potential Phase 1 Currents in the Brugada Syndrome Control hormonal de las corrientes de la fase 1 del potencial de acción cardíaco en el síndrome de Brugada MARIANA ARGENZIANO 1,2, GISELA TISCORNIA 1,2, ROSALIA MORETTA 1, CARLOS E. AMORENA 1,2, EDUARDO GARCIA GRAS 1,2 ABSTRACT Introduction: The Brugada syndrome is an inherited channelopathy with autosomal dominant genotype transmission pat- tern presenting marked gender bias in phenotype expression, with a male to female ratio of 9:1. A cellular model of the disease suggests a heterogeneous distribution in the phase 1 amplitude of the ventricular action potential as the origin for the development of the arrhythmogenic substrate. Objective: The aim of this study was to investigate the role of androgens on the cardiac action potential phase 1 regulation and its electrophysiological consequences in an experimental murine model of Brugada syndrome.
    [Show full text]
  • RT² Profiler PCR Array (96-Well Format and 384-Well [4 X 96] Format)
    RT² Profiler PCR Array (96-Well Format and 384-Well [4 x 96] Format) Mouse Neuronal Ion Channels Cat. no. 330231 PAMM-036ZA For pathway expression analysis Format For use with the following real-time cyclers RT² Profiler PCR Array, Applied Biosystems® models 5700, 7000, 7300, 7500, Format A 7700, 7900HT, ViiA™ 7 (96-well block); Bio-Rad® models iCycler®, iQ™5, MyiQ™, MyiQ2; Bio-Rad/MJ Research Chromo4™; Eppendorf® Mastercycler® ep realplex models 2, 2s, 4, 4s; Stratagene® models Mx3005P®, Mx3000P®; Takara TP-800 RT² Profiler PCR Array, Applied Biosystems models 7500 (Fast block), 7900HT (Fast Format C block), StepOnePlus™, ViiA 7 (Fast block) RT² Profiler PCR Array, Bio-Rad CFX96™; Bio-Rad/MJ Research models DNA Format D Engine Opticon®, DNA Engine Opticon 2; Stratagene Mx4000® RT² Profiler PCR Array, Applied Biosystems models 7900HT (384-well block), ViiA 7 Format E (384-well block); Bio-Rad CFX384™ RT² Profiler PCR Array, Roche® LightCycler® 480 (96-well block) Format F RT² Profiler PCR Array, Roche LightCycler 480 (384-well block) Format G RT² Profiler PCR Array, Fluidigm® BioMark™ Format H Sample & Assay Technologies Description The Mouse Neuronal Ion Channels RT² Profiler PCR Array was developed to profile expression of a panel of 84 genes encoding neuroscience-related ion channels and transporters. The genes represented on the array are listed below, grouped according to their functional and structural features. Included are calcium channels, potassium channels, sodium channels, chloride channels, and transporters. Using real-time PCR, you can easily and reliably analyze expression of a focused panel of genes related to the neuronal ion channels and transporters with this array.
    [Show full text]
  • Supplemental Figure 1
    Supplemental Figure 1 la avb san ra avn lv Tbx3 Tbx5 Scn5a Supplemental Figure 1 Cartoon depicting expression patterns of Tbx3, Tbx5 and Scn5a in the heart from fetal stages onwards. Tbx5 activates Scn5a in the heart. The pattern of Scn5a is broader than that of Tbx5, indicating other activators expressed in broader patterns are involved in Scn5a activation. Note the absence of expression of Scn5a in the Tbx3+ (red) and Tbx5+ (purple) region of the sinus node (san), internodal region, atrioventricular node (avn) and atrioventricular canal myocardium, indicating that the repressive function of Tbx3 is dominant in these parts of the heart. avb, atrioventricular bundle; l/ra, left/right atrium; l/rv, left/right ventricle. Supplemental Figure 2 20 kbp 30 Tbx3 3 25 Gata4 3 75 5 - Nkx2 9 50 p300 0 Tbx5* Hopx Gata4* Nkx2-5* P300# P300$ Pol2$ Supplemental Figure 2 Alignment of ChIP-seq datasets from mouse heart (Tbx3, red; Gata4, blue; Nkx2-5, green; p300, orange) described in this manuscript, with other published datasets in the vicinity of Hopx, a gene involved in conduction system function (1). Overlap in multiple datasets was used as selection criterion for enhancer activity screening (Figure 1C). Supplemental Figure 3 Tbx5 TRANSFAC GATA1 TRANSFAC NKX2-5 JASPAR T JASPAR GATA1 JASPAR NKX3-2 JASPAR HL1 Tbx5 ChIP-seq motif HL1 Gata4 ChIP-seq motif HL1 Nkx2-5 ChIP-seq motif TBX3 ChIP-seq motif Gata4 ChIP-seq motif Nkx2-5 ChIP-seq motif Supplemental Figure 3 Motif discovery analysis for ChIP-seq data. MEME motif discovery analysis for Tbx3 ChIP-seq data, Gata4 ChIP- seq data and Nkx2-5 ChIP-seq data (bottom row) compared to published consensus sequences available from TRANSFAC (2), JASPAR (3,4) and the recently published HL-1 ChIP-seq derived binding sites (5).
    [Show full text]