# Novel Roles of Protein phosphatase 2A in Cardiac Arrhythmia

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2024 · $635,106

## Abstract

Project Summary
 Sudden cardiac death and arrhythmias account for ~15-20% of all deaths worldwide. Voltage gated sodium
channels (Nav) in heart are major regulators of myocyte excitability and cardiac function. The Nav channel current
(INa) is a large amplitude and short duration inward current that is regulated by rapid channel activation and
immediate inactivation. However, a small late component of this current (INa,L) is present at baseline but increases
in response to heightened adrenergic challenge and has been correlated with fatal forms of congenital and
acquired arrhythmia. The majority of work on Nav1.5 has focused on molecular pathways for positive regulation
of INa,L. However, less is known about the pathways for negative regulation. These pathways are critical and can
be targeted to alter the pathogenic INa,L in potentially fatal forms of arrhythmia.
 My previous work identified a key pathway for INa,L regulation via the B56α regulatory subunit of protein
phosphatase 2A (PP2A). My previous and current data support that: 1) B56α co-localizes with Nav1.5 in the
heart at the intercalated disc, along with ankyrin-G and CaMKIIδ, 2) PP2A activity is regulated by the specific
regulatory subunit (B56α) and 3) activation of PP2A through modulation of B56α is sufficient to regulate Nav1.5
activity and resist the increase in INa,L following adrenergic challenge. Our work illustrates a key role of B56α in
INa,L regulation as well as the potential for targeting this pathway in arrhythmias. However, the field has been
limited by two key issues: 1) the lack of selective and inducible in vivo models to selectively impact key PP2A
regulatory proteins, and 2) the lack of molecules that selectively target PP2A activity in vivo.
 For this proposal, we have generated two novel tools to identify the impact of PP2A-B56α on cardiac action
potential and arrhythmias in vivo. First, we have created the first in vivo model to both constitutively as well as
inducibly impact local PP2A regulatory subunit (B56α) function, and thus cardiac PP2A activity. This model has
the impact in a field where work was limited to in vitro studies or non-selective activation or protein reduction.
Second, we have identified a new molecule to directly test the in vivo impact of PP2A activation in disease. Our
collaborators at Ohio State have synthesized a new molecule and have shown that this molecule increases
PP2A activity. Our preliminary data support our central hypothesis that PP2A, via the B56α regulatory subunit,
regulates the intercalated disc Nav1.5 to counteract CaMKII-dependent phosphorylation in disease. Further, we
hypothesize that molecules that selectively modulate the PP2A-B56α holoenzyme will impact altered INa,L in heart
disease. Combining molecular, biochemical, pharmacological, patch clamping and Ca2+ imaging approaches,
we will: 1) define the functional role of PP2A-B56α signaling complex in primary myocytes, 2) determine the
effects of PP2A-B56α regulation on ...

## Key facts

- **NIH application ID:** 10943347
- **Project number:** 1R01HL175380-01
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Mona El Refaey
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $635,106
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10943347

## Citation

> US National Institutes of Health, RePORTER application 10943347, Novel Roles of Protein phosphatase 2A in Cardiac Arrhythmia (1R01HL175380-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10943347. Licensed CC0.

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