Ion channel messenger RNA processing defects and arrhythmia

Current Biomarker Findings Dovepress open access to scientific and medical research Review Open Access Full Text Article Current Biomarker Findings downloaded from https://www.dovepress.com/ by 88.198.20.149 on 05-May-2021 For personal use only. Ion channel messenger RNA processing defects and arrhythmia This article was published in the following Dove Press journal: Current Biomarker Findings 24 November 2014 Number of times this article has been viewed Anyu Zhou Samuel C Dudley Jr Lifespan Cardiovascular Research Center, The Warren Alpert School of Medicine, Brown University, and Providence Veterans Administration Medical Center, Providence, RI, USA Introduction Correspondence: Samuel C Dudley Jr Lifespan Cardiovascular Institute, Ruth and Paul Levinger Chair in Medicine, The Warren Alpert Medical School of Brown University, 593 Eddy Street, APC 730, Providence, RI 02903, USA Tel +1 401 444 5328 Fax +1 401 444 4652 Email Cardiac arrhythmias cause a significant number of deaths worldwide,1 and the risk of arrhythmias is inversely related to cardiac contractile function. Arrhythmia refers to any deviation from the normal pattern of the heartbeat, encompassing abnormalities of rate, regularity, site of impulse origin, and sequence of activation. The mechanisms of arrhythmia caused by ion channel defects are complicated and have been well reviewed in other articles.2–4 In short, normal cardiac excitation and relaxation involves a delicate balance of complex dynamic interactions between ionic currents passing through a variety of membrane channels. Cardiac excitation reflects membrane depolarization of cardiac myocytes, primarily because of the activation of voltage-dependent Na+ channels that underlie the action potential upstroke. Activation is then followed by a long depolarized plateau phase that permits Ca2+-induced Ca2+ release from the sarcoplasmic reticulum, binding of Ca2+ to contractile proteins on the sarcomeres, and coordinated contraction. Repolarization follows secondary to the time-dependent and voltage-dependent activation of repolarizing potassium currents. Relaxation of contraction is coupled to the electrical repolarization phase, which allows filling of the ventricles prior to the next excitation. Abnormal activity of cardiac ion channels can disrupt this electrical sequence and cause arrhythmia. 151 submit your manuscript | www.dovepress.com Current Biomarker Findings 2014:4 151–160 Dovepress © 2014 Zhou and Dudley. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php http://dx.doi.org/10.2147/CBF.S37417 Powered by TCPDF (www.tcpdf.org) Abstract: Messenger RNA (mRNA) processing is an essential step for the expression of most eukaryote genes. Ion channels are critical for proper electrical activity in the heart, and perturbations of these channels are known to cause arrhythmia. Recently, mRNA processing defects have been shown to contribute to altered ion channel activity and arrhythmogenesis. Abnormal pre-mRNA splicing of cardiac ion channels, including the cardiac sodium channel, potassium channels, and calcium channels, because of mutations of the cis-elements within the RNA or abnormal expression of splicing factors, has been documented to contribute to arrhythmic risk. In addition to pre-mRNA splicing, other mRNA processing events, such as 3′-end formation and mRNA turnover, are also disrupted in cardiac diseases, such as congenital heart disease caused by mutation at the 3′-untranslated region of GATA4. mRNA stability is also dysregulated by altered expression of microRNAs in atrial fibrillation. In this review, we discuss our current understanding of how mRNA processing defects contribute to the risk of arrhythmias and how monitoring the products of abnormal processing may lead to diagnostic tests for arrhythmic risk. Keywords: messenger RNA, arrhythmia, sudden death, ion channels, biomarkers Dovepress Current Biomarker Findings downloaded from https://www.dovepress.com/ by 88.198.20.149 on 05-May-2021 For personal use only. Zhou and Dudley Abnormal activity of cardiac ion channels has many causes, including amino acid sequence changes and accompanying functional abnormalities caused by genetic defects, mutations, and polymorphisms.5–7 The expression level of ion channels can also be altered by dysregulation of transcription, post-transcriptional RNA processing, and protein degradation.8–11 Cardiac contractile dysfunction is associated with ion channel changes,11 and these ion channel changes are thought to contribute to increased arrhythmic risk. Genetic and epigenetic alterations have been linked to arrhythmias.12–15 Now, it is being recognized that defects of messenger RNA (mRNA) processing can cause arrhythmogenesis (Table 1). This review focuses on mRNA processing, especially pre-mRNA splicing and mRNA stability and its impact on cardiac arrhythmias. Elucidation of mRNA processing defects is providing insights into the fundamental mechanisms of cardiac arrhythmias as well as the identification of possible targets for developing novel antiarrhythmic therapeutics to correct the electrical remodeling associated with heart disease. mRNA processing When a eukaryotic gene is transcribed, the initial primary transcript synthesized by RNA polymerase II must be extensively modified before it can leave the nucleus and be translated into protein. This process includes 5′ capping, 3′-end polyadenylation, editing, and splicing (Figure 1). These nuclear processing steps, which largely determine the fate of the resulting transcript, require a large set of proteins, adding a layer of potential regulation that can affect export, localization, translation, and stability of the mature RNA.16 This processing allows the cell to finetune gene expression in a fast, precise, and cost-effective manner.17 RNA processing is tightly coupled with transcription. It begins while RNA polymerase II is in the process of transcribing the gene into RNA. This processing affects not only protein-coding RNA but also small nuclear RNAs, microRNAs (miRNAs), and other noncoding RNAs.18–20 The C-terminal domain of RNA polymerase II provides the basis for the coupling between transcription and RNA processing.18 The first step of RNA processing is the addition of an inverted guanosine to the 5′ end, and methylation of this guanosine to create a “cap” that marks the beginning of the mRNA. Capping helps protect the transcript degradation from (...truncated)