Cardiac excitability is finely controlled by a combination of depolarizing and repolarizing currents. Fine regulation and dysregulation of a host of inward and outward ion currents are thought to play a major role in numerous clinically relevant cardiac arrhythmias. In fact, it is now well established that even subtle alterations of the cardiac action potential properties caused by dysfunction of ion channels, may lead to cardiac disorders known as channelopathies. Classic formalism teaches that ion channels function independently of each other according to their individual time- and voltage- dependent biophysical properties. This is the basis for computer models developed to understand single cell electrophysiological behavior. However, in Brugada syndrome (BrS), a form of genetic arrhythmia caused by mutations in the sodium channel, functional interaction between channels mediating potassium (Ito) and sodium (INa) currents has been suggested to be involved in the two main arrhythmogenic mechanisms: repolarization disorder and conduction disorder hypothesis. Thus, is it possible that the regulation of ion channel subunits mediating these two major currents of the cardiac action potential is coordinated? Notably, our recent work was the first to support this provocative idea that the expression of the depolarizing sodium channel and the repolarizing potassium channel Ito may share a common, yet to be identified, regulatory mechanism. Following gene silencing of KChIP2, an accessory subunit of Ito, the applicant found that the expression of Ito and INa was abolished producing a non-excitable cardiac myocytes. This suggested that the regulation of ion channel mediating these two major currents could be coordinated. This would represent a paradigm-shifting concept regarding ion channels expression and regulation. Therefore, we hypothesize that KChIP2 controls the expression of depolarizing (INa) and repolarizing (Ito) currents through multiple regulatory mechanisms.
The specific aims of this proposal are to: 1. Identify genes modulated by KChIP2. 2. Determine if the regulation of INa and Ito involves microRNA(s). 3. Define the role of KChIP2 miRNA-dependent regulation in cardiac pathology. The delineation of the molecular basis of this regulation is essential for an accurate understanding of cardiac ventricular depolarization and repolarization and its derangements that are associated with lethal ventricular arrhythmias. Further functional dissection of KChIP2 will provide insight into numerous aspects of cardiac function will illuminate the role of the KChIP2 family of proteins in disease and likely unveil novel paradigms for ion channel function in health and disease.

Public Health Relevance

This project will provide new critical insights into the functional association and regulation of ionic currents that are essential to normal depolarization and repolarization in the heart. Understanding the mechanisms of regulation of sodium and potassium currents will contribute to our understanding of their involvement in diseased states.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL096962-01A2
Application #
7993375
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Wang, Lan-Hsiang
Project Start
2010-07-06
Project End
2014-06-30
Budget Start
2010-07-06
Budget End
2011-06-30
Support Year
1
Fiscal Year
2010
Total Cost
$392,500
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Nassal, Michelle M J; Wan, Xiaoping; Dale, Zack et al. (2017) Mild hypothermia preserves myocardial conduction during ischemia by maintaining gap junction intracellular communication and Na+channel function. Am J Physiol Heart Circ Physiol 312:H886-H895
Nassal, Drew M; Wan, Xiaoping; Liu, Haiyan et al. (2017) KChIP2 regulates the cardiac Ca2+ transient and myocyte contractility by targeting ryanodine receptor activity. PLoS One 12:e0175221
Sun, Yu; Timofeyev, Valeriy; Dennis, Adrienne et al. (2017) A Singular Role of IK1 Promoting the Development of Cardiac Automaticity during Cardiomyocyte Differentiation by IK1 -Induced Activation of Pacemaker Current. Stem Cell Rev 13:631-643
Nassal, Drew M; Wan, Xiaoping; Liu, Haiyan et al. (2017) KChIP2 is a core transcriptional regulator of cardiac excitability. Elife 6:
Sattayaprasert, Prasongchai; Nassal, Drew M; Wan, Xiaoping et al. (2016) Mesenchymal stem cells suppress cardiac alternans by activation of PI3K mediated nitroso-redox pathway. J Mol Cell Cardiol 98:138-45
Nassal, Drew M; Wan, Xiaoping; Liu, Haiyan et al. (2016) Myocardial KChIP2 Expression in Guinea Pig Resolves an Expanded Electrophysiologic Role. PLoS One 11:e0146561
Plummer, Bradley N; Liu, Haiyan; Wan, Xiaoping et al. (2015) Targeted antioxidant treatment decreases cardiac alternans associated with chronic myocardial infarction. Circ Arrhythm Electrophysiol 8:165-73
Dennis, Adrienne T; Wang, Lu; Wan, Hanlin et al. (2012) Molecular determinants of pentamidine-induced hERG trafficking inhibition. Mol Pharmacol 81:198-209
Dennis, Adrienne T; Nassal, Drew; Deschenes, Isabelle et al. (2011) Antidepressant-induced ubiquitination and degradation of the cardiac potassium channel hERG. J Biol Chem 286:34413-25