# Cardiac Ion Channel Regulation

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2021 · $500,989

## Abstract

Project Summary
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 function...

## Key facts

- **NIH application ID:** 10113659
- **Project number:** 5R01HL096962-08
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Isabelle Deschenes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $500,989
- **Award type:** 5
- **Project period:** 2010-07-06 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10113659

## Citation

> US National Institutes of Health, RePORTER application 10113659, Cardiac Ion Channel Regulation (5R01HL096962-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10113659. Licensed CC0.

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