Mutations of Voltage-Gated Ionic Channels and Risk of Severe Cardiac Arrhythmias
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Paramyotonia Congenita
Paramyotonia congenita Description Paramyotonia congenita is a disorder that affects muscles used for movement (skeletal muscles). Beginning in infancy or early childhood, people with this condition experience bouts of sustained muscle tensing (myotonia) that prevent muscles from relaxing normally. Myotonia causes muscle stiffness that typically appears after exercise and can be induced by muscle cooling. This stiffness chiefly affects muscles in the face, neck, arms, and hands, although it can also affect muscles used for breathing and muscles in the lower body. Unlike many other forms of myotonia, the muscle stiffness associated with paramyotonia congenita tends to worsen with repeated movements. Most people—even those without muscle disease—feel that their muscles do not work as well when they are cold. This effect is dramatic in people with paramyotonia congenita. Exposure to cold initially causes muscle stiffness in these individuals, and prolonged cold exposure leads to temporary episodes of mild to severe muscle weakness that may last for several hours at a time. Some older people with paramyotonia congenita develop permanent muscle weakness that can be disabling. Frequency Paramyotonia congenita is an uncommon disorder; it is estimated to affect fewer than 1 in 100,000 people. Causes Mutations in the SCN4A gene cause paramyotonia congenita. This gene provides instructions for making a protein that is critical for the normal function of skeletal muscle cells. For the body to move normally, skeletal muscles must tense (contract) and relax in a coordinated way. Muscle contractions are triggered by the flow of positively charged atoms (ions), including sodium, into skeletal muscle cells. The SCN4A protein forms channels that control the flow of sodium ions into these cells. -
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. -
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. -
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. -
Examining the Regulation of Kv7 K+ Channels in Airway Smooth Muscle Cells and Their Potential As Novel Therapeutic Targets for the Treatment of Asthma
Loyola University Chicago Loyola eCommons Dissertations Theses and Dissertations 2017 Examining the Regulation of Kv7 K+ Channels in Airway Smooth Muscle Cells and Their Potential as Novel Therapeutic Targets for the Treatment of Asthma Jennifer Haick Loyola University Chicago Follow this and additional works at: https://ecommons.luc.edu/luc_diss Part of the Pharmacology Commons Recommended Citation Haick, Jennifer, "Examining the Regulation of Kv7 K+ Channels in Airway Smooth Muscle Cells and Their Potential as Novel Therapeutic Targets for the Treatment of Asthma" (2017). Dissertations. 2588. https://ecommons.luc.edu/luc_diss/2588 This Dissertation is brought to you for free and open access by the Theses and Dissertations at Loyola eCommons. It has been accepted for inclusion in Dissertations by an authorized administrator of Loyola eCommons. For more information, please contact [email protected]. This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License. Copyright © 2017 Jennifer Haick LOYOLA UNIVERSITY CHICAGO EXAMINING THE REGULATION OF Kv7 K+ CHANNELS IN AIRWAY SMOOTH MUSCLE CELLS AND THEIR POTENTIAL AS NOVEL THERAPEUTIC TARGETS FOR THE TREATMENT OF ASTHMA A DISSERTATION SUBMITTED TO THE FACULTY OF THE GRADUATE SCHOOL IN CANDIDACY FOR THE DEGREE OF DOCTOR OF PHILOSOPHY PROGRAM IN MOLECULAR PHARMACOLOGY AND THERAPEUTICS BY JENNIFER HAICK CHICAGO, IL MAY 2017 ACKNOWLEDGEMENTS I would like to take a moment to thank all of the people who have helped and supported me these past years while I have been working towards my Ph.D. First and foremost, I would like to thank Dr. Kenneth Byron for accepting me into his lab and for his mentorship these past years. -
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. -
Emerging Roles for Multifunctional Ion Channel Auxiliary Subunits in Cancer T ⁎ Alexander S
Cell Calcium 80 (2019) 125–140 Contents lists available at ScienceDirect Cell Calcium journal homepage: www.elsevier.com/locate/ceca Emerging roles for multifunctional ion channel auxiliary subunits in cancer T ⁎ Alexander S. Hawortha,b, William J. Brackenburya,b, a Department of Biology, University of York, Heslington, York, YO10 5DD, UK b York Biomedical Research Institute, University of York, Heslington, York, YO10 5DD, UK ARTICLE INFO ABSTRACT Keywords: Several superfamilies of plasma membrane channels which regulate transmembrane ion flux have also been Auxiliary subunit shown to regulate a multitude of cellular processes, including proliferation and migration. Ion channels are Cancer typically multimeric complexes consisting of conducting subunits and auxiliary, non-conducting subunits. Calcium channel Auxiliary subunits modulate the function of conducting subunits and have putative non-conducting roles, further Chloride channel expanding the repertoire of cellular processes governed by ion channel complexes to processes such as trans- Potassium channel cellular adhesion and gene transcription. Given this expansive influence of ion channels on cellular behaviour it Sodium channel is perhaps no surprise that aberrant ion channel expression is a common occurrence in cancer. This review will − focus on the conducting and non-conducting roles of the auxiliary subunits of various Ca2+,K+,Na+ and Cl channels and the burgeoning evidence linking such auxiliary subunits to cancer. Several subunits are upregu- lated (e.g. Cavβ,Cavγ) and downregulated (e.g. Kvβ) in cancer, while other subunits have been functionally implicated as oncogenes (e.g. Navβ1,Cavα2δ1) and tumour suppressor genes (e.g. CLCA2, KCNE2, BKγ1) based on in vivo studies. The strengthening link between ion channel auxiliary subunits and cancer has exposed these subunits as potential biomarkers and therapeutic targets. -
KCND3 Potassium Channel Gene Variant Confers Susceptibility to Electrocardiographic Early Repolarization Pattern
KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern Alexander Teumer, … , Elijah R. Behr, Wibke Reinhard JCI Insight. 2019. https://doi.org/10.1172/jci.insight.131156. Clinical Medicine In-Press Preview Cardiology Genetics Graphical abstract Find the latest version: https://jci.me/131156/pdf 1 KCND3 potassium channel gene variant confers susceptibility to 2 electrocardiographic early repolarization pattern 3 Alexander Teumer1,2*, Teresa Trenkwalder3*, Thorsten Kessler3, Yalda Jamshidi4, Marten E. van den 4 Berg5, Bernhard Kaess6, Christopher P. Nelson7,8, Rachel Bastiaenen9, Marzia De Bortoli10, 5 Alessandra Rossini10, Isabel Deisenhofer3, Klaus Stark11, Solmaz Assa12, Peter S. Braund7,8, Claudia 6 Cabrera13,14,15, Anna F. Dominiczak16, Martin Gögele10, Leanne M. Hall7,8, M. Arfan Ikram5, Maryam 7 Kavousi5, Karl J. Lackner17,18, Lifelines Cohort Study19, Christian Müller20, Thomas Münzel18,21, 8 Matthias Nauck2,22, Sandosh Padmanabhan16, Norbert Pfeiffer23, Tim D. Spector24, Andre G. 9 Uitterlinden5, Niek Verweij12, Uwe Völker2,25, Helen R. Warren13,14, Mobeen Zafar12, Stephan B. 10 Felix2,26, Jan A. Kors27, Harold Snieder28, Patricia B. Munroe13,14, Cristian Pattaro10, Christian 11 Fuchsberger10, Georg Schmidt29,30, Ilja M. Nolte28, Heribert Schunkert3,30, Peter Pramstaller10, Philipp 12 S. Wild31, Pim van der Harst12, Bruno H. Stricker5, Renate B. Schnabel20, Nilesh J. Samani7,8, 13 Christian Hengstenberg32, Marcus Dörr2,26, Elijah R. Behr33, Wibke Reinhard3 14 15 16 1 Institute -
Variants in the KCNE1 Or KCNE3 Gene and Risk of Ménière’S Disease: a Meta-Analysis
Journal of Vestibular Research 25 (2015) 211–218 211 DOI 10.3233/VES-160569 IOS Press Variants in the KCNE1 or KCNE3 gene and risk of Ménière’s disease: A meta-analysis Yuan-Jun Li, Zhan-Guo Jin and Xian-Rong Xu∗ The Center of Clinical Aviation Medicine, General Hospital of Air Force, Beijing, China Received 1 August 2015 Accepted 8 December 2015 Abstract. BACKGROUND: Ménière’s disease (MD) is defined as an idiopathic disorder of the inner ear characterized by the triad of tinnitus, vertigo, and sensorineural hearing loss. Although many studies have evaluated the association between variants in the KCNE1 or KCNE3 gene and MD risk, debates still exist. OBJECTIVE: Our aim is to evaluate the association between KCNE gene variants, including KCNE1 rs1805127 and KCNE3 rs2270676, and the risk of MD by a systematic review. METHODS: We searched the literature in PubMed, SCOPUS and EMBASE through May 2015. We calculated pooled odds ra- tios (OR) and 95% confidence intervals (CIs) using a fixed-effects model or a random-effects model for the risk to MD associated with different KCNE gene variants. The heterogeneity assumption decided the effect model. RESULTS: A total of three relevant studies, with 302 MD cases and 515 controls, were included in this meta-analysis. The results indicated that neither the KCNE1 rs1805127 variant (for G vs. A: OR = 0.724, 95%CI 0.320, 1.638, P = 0.438), nor the KCNE3 rs2270676 variant (for T vs. C: OR = 0.714, 95%CI 0.327, 1.559, P = 0.398) was associated with MD risk. -
Investigation of Candidate Genes and Mechanisms Underlying Obesity
Prashanth et al. BMC Endocrine Disorders (2021) 21:80 https://doi.org/10.1186/s12902-021-00718-5 RESEARCH ARTICLE Open Access Investigation of candidate genes and mechanisms underlying obesity associated type 2 diabetes mellitus using bioinformatics analysis and screening of small drug molecules G. Prashanth1 , Basavaraj Vastrad2 , Anandkumar Tengli3 , Chanabasayya Vastrad4* and Iranna Kotturshetti5 Abstract Background: Obesity associated type 2 diabetes mellitus is a metabolic disorder ; however, the etiology of obesity associated type 2 diabetes mellitus remains largely unknown. There is an urgent need to further broaden the understanding of the molecular mechanism associated in obesity associated type 2 diabetes mellitus. Methods: To screen the differentially expressed genes (DEGs) that might play essential roles in obesity associated type 2 diabetes mellitus, the publicly available expression profiling by high throughput sequencing data (GSE143319) was downloaded and screened for DEGs. Then, Gene Ontology (GO) and REACTOME pathway enrichment analysis were performed. The protein - protein interaction network, miRNA - target genes regulatory network and TF-target gene regulatory network were constructed and analyzed for identification of hub and target genes. The hub genes were validated by receiver operating characteristic (ROC) curve analysis and RT- PCR analysis. Finally, a molecular docking study was performed on over expressed proteins to predict the target small drug molecules. Results: A total of 820 DEGs were identified between -
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. -
Expression Profiling of Ion Channel Genes Predicts Clinical Outcome in Breast Cancer
UCSF UC San Francisco Previously Published Works Title Expression profiling of ion channel genes predicts clinical outcome in breast cancer Permalink https://escholarship.org/uc/item/1zq9j4nw Journal Molecular Cancer, 12(1) ISSN 1476-4598 Authors Ko, Jae-Hong Ko, Eun A Gu, Wanjun et al. Publication Date 2013-09-22 DOI http://dx.doi.org/10.1186/1476-4598-12-106 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Ko et al. Molecular Cancer 2013, 12:106 http://www.molecular-cancer.com/content/12/1/106 RESEARCH Open Access Expression profiling of ion channel genes predicts clinical outcome in breast cancer Jae-Hong Ko1, Eun A Ko2, Wanjun Gu3, Inja Lim1, Hyoweon Bang1* and Tong Zhou4,5* Abstract Background: Ion channels play a critical role in a wide variety of biological processes, including the development of human cancer. However, the overall impact of ion channels on tumorigenicity in breast cancer remains controversial. Methods: We conduct microarray meta-analysis on 280 ion channel genes. We identify candidate ion channels that are implicated in breast cancer based on gene expression profiling. We test the relationship between the expression of ion channel genes and p53 mutation status, ER status, and histological tumor grade in the discovery cohort. A molecular signature consisting of ion channel genes (IC30) is identified by Spearman’s rank correlation test conducted between tumor grade and gene expression. A risk scoring system is developed based on IC30. We test the prognostic power of IC30 in the discovery and seven validation cohorts by both Cox proportional hazard regression and log-rank test.