Cardiac arrhythmias are a leading cause of morbidity and mortality in developed nations, resulting in more than 300,000 deaths per year in the U.S. alone. These arrhythmias are frequently associated with acquired heart diseases, notably cardiac hypertrophy and heart failure (HF), where the dysregulation of a host of ion channels and transporters is observed. One of the most consistent changes frequently associated with compromised repolarization, is selective reduction in the transient outward potassium current Ito. Ito is generated primarily by the voltage-gated potassium (Kv) channel, Kv4, and its interacting auxiliary subunit known as K Channel Interacting Protein 2 (KChIP2). Under hypertrophy and HF there is consistent loss of KChIP2, thought to cause the reduction in Ito. Intriguingly, the loss in KChIP2 expression has been observed to be one of the earliest and most consistent remodeling events in HF development. The commonality and early state of this remodeling begins to suggest KChIP2 loss might not just be one of the casualties during disease progression, but may represent an initiating factor driving pathogenesis. Emerging evidence suggests KChIP2 may not be limited to cell surface regulation of Kv4. Indeed, since its original discovery, there has been an expansion in the roles of KChIP2 in cardiac ion channel function including modulation of Na, L-type Ca, and Kv1.5 channels. In total, there are four KChIP genes (KChIP1-4) with many alternatively spliced isoforms. Interestingly, KChIP3 (found in the brain), calsenilin and DREAM are encoded by a single gene. These names are the result of three independent discoveries due to different roles: modulation of Kv channels, regulation of the protein presenilin, and critically, calcium-sensitive transcriptional repression through binding to DRE (downstream regulatory element) sequences of genes. While KChIP2 is the only isoform found in the heart, given the homology it shares with KChIP3, it led us to hypothesize that KChIP2 could also perform multiple functions. Indeed, during the previous funding period, we identified a significantly expanded importance of KChIP2 in the heart. We demonstrated novel functions for KChIP2 in regulating calcium currents and RyR2. Importantly, we demonstrated a novel role for KChIP2 where it could regulate the genes at the source of INa and Ito by acting, much like KChIP3/DREAM, as a transcriptional repressor targeting a family of microRNAs. In this renewal, we will elucidate in aim 1 the role of KChIP2 as a transcriptional repressor.
In aim 2, we will determine the control mechanisms for KChIP2 trafficking between cytoplasm and nucleus. And in aim 3, we will elucidate how chronic stress affects KChIP2 distribution and function in cardiac myocytes. Collectively, the outcomes of these investigations will demonstrate that KChIP2 actions are dramatically more expansive than modulation of Kv4 channels alone, suggesting that these other KChIP2 functions can be potent contributors to adverse remodeling events characterized in the diseased heart.

Public Health Relevance

Acquired heart diseases, like cardiac hypertrophy and heart failure, often result in arrhythmias due to changes in a host of ion channels. Change in the accessory subunit KChIP2 is a hallmark of the diseased heart. Here we aim to delineate novel roles for KChIP2 in the heart and how it can regulate cardiac excitability through multiple pathways. In this renewal, we will further expand on the role of KChIP2 as a transcriptional repressor and determine what modulates its location and function as either an ion channel modulator or a transcriptional repressor under normal and disease states.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL096962-05
Application #
9542573
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Balijepalli, Ravi C
Project Start
2010-07-06
Project End
2022-02-28
Budget Start
2018-04-01
Budget End
2019-02-28
Support Year
5
Fiscal Year
2018
Total Cost
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
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