# Local RyR2 Control

> **NIH NIH F31** · RUSH UNIVERSITY MEDICAL CENTER · 2021 · $46,036

## Abstract

Ethanol (ETOH) has cardio toxic actions and acute ETOH exposure can lead to cardiomyopathy and
death. Acute ETOH can result in irregular heart rhythms and atrial fibrillation (AF). A third of all new-onset AF
cases are related to ETOH intoxication (1). In clinics, AF following acute consumption of high amounts of
ETOH (binge drinking) underlies Holiday Heart Syndrome (HHS), unexpected AF onset. Logically, ETOH
abstinence will reduce AF risk but the failure rate of abstinence is high and consequently AF recurrence is
common in ETOH abusers. Breaking the acute ETOH → AF link would be beneficial considering the clinical
mantra “AF begets AF” (i.e. repeated AF bouts progress to persistent AF) (2). There are no therapeutic
strategies (besides abstinence) that prevent or treat acute ETOH-driven AF. One obstacle is that few details
about the molecular mechanisms linking acute ETOH exposure and AF are unknown. Our group recently
discovered acute ETOH evokes AF by activating the stress-activated c-Jun N-terminal kinase (JNK) (3). The
activated JNK then phosphorylates Ca2+ /calmodulin-dependent protein kinase II (CaMKII) which in turn
phosphorylates the cardiac ryanodine receptor (RyR2), increasing the RyR2’s open probability (Po). This
signaling cascade ultimately promotes diastolic RyR2-mediated spontaneous intracellular Ca release events
(sparks/waves) that initiate AF (3). Our group also recently found that Carvedilol, an FDA-approved β-
adrenergic blocker, has a direct action on RyR2 openings (4) and this limits the spontaneous diastolic Ca
waves that cause Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), a deadly ventricular
arrhythmia. Interestingly, CPVT and acute ETOH-driven AF occur in structurally normal hearts and have a
common pathophysiological origin, abnormal spontaneous RyR-mediated diastolic Ca release. Finding ways to
limit these spontaneous events thus has broad therapeutic promise and agents originally developed to address
CPVT may also help prevent/treat acute ETOH-driven AF. The following hypothesis will be tested. Acute
ETOH exposure incrementally alters diastolic RyR2 function by acting on RyR2-CamKII-JNK2 protein
complex resident on the sarcoplasmic reticulum (SR) membrane and novel non- 𝛽 blocking Carvedilol
derivatives can normalize acute ETOH-driven RyR2 dysfunction. A multidisciplinary approach will be used
to test this hypothesis by addressing the following specific aims. 1) Define molecular mechanism(s) linking JNK
activation and single RyR2 function. 2) Test RyR-targeted intervention options to limit the abnormal
spontaneous diastolic SR Ca release caused by acute ETOH exposure and underlying HHS. Training Plan:
The applicant will master the techniques of single ion channel recordings, binding assays and intracellular Ca
imaging. Applicant will present her research at local, national and international forums and her training will take
place at Rush University Medical Center in the department of Physiology and B...

## Key facts

- **NIH application ID:** 10116178
- **Project number:** 5F31HL151059-02
- **Recipient organization:** RUSH UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Catherine Carvajal
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 5
- **Project period:** 2020-01-24 → 2022-01-23

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10116178

## Citation

> US National Institutes of Health, RePORTER application 10116178, Local RyR2 Control (5F31HL151059-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10116178. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*