# Cardiac Calsequestrin (Casq2) function in excitation-contraction coupling and cardiac arrhythmias

> **NIH NIH F30** · VANDERBILT UNIVERSITY · 2021 · $48,294

## Abstract

PROJECT SUMMARY/ABSTRACT
Calsequestrin-2 (Casq2) is a high capacity, low affinity calcium (Ca) binding protein located in the junctional
sarcoplasmic reticulum (SR) of cardiac myocytes. As the major SR Ca buffer, Casq2 interacts with the ryanodine
receptor (RyR2), a Ca release channel, to regulate the amount of Ca that is released during the excitation-
contraction (EC) coupling cycle, a process that couples electrical activation to mechanical force (i.e. a heartbeat).
Alterations in EC coupling can cause both contractile dysfunction and cardiac arrhythmias. Reduction or loss of
Casq2 due to mutations causes a severe genetic arrhythmia syndrome known as catecholaminergic polymorphic
ventricular tachycardia (CPVT). Genetic variants of Casq2 have also been associated with sudden cardiac death
and heart failure in patients with coronary artery disease, while overexpression of Casq2 causes hypertrophy
and heart failure in mice. Casq2-linked CPVT is usually autosomal-recessive, with mutations resulting in either
a severe reduction or complete loss of Casq2 protein. As a result, SR Ca buffering is reduced, which leads to
spontaneous Ca release and arrhythmias. In 2016, a genetic analysis conducted in a family that had an
autosomal dominant inheritance of CPVT uncovered a novel missense mutation (K180R) within Casq2. This
was the first autosomal dominant mutation found in Casq2. Initial studies in heterozygous K180R knock-in mice
demonstrate that protein levels of Casq2 are normal but mice exhibit CPVT when stressed. This suggests that
Casq2-K180R causes CPVT by a different mechanism than previously reported autosomal-recessive Casq2
mutations. I hypothesize that Casq2-K180R causes CPVT by disrupting its ability to regulate RyR2 Ca
release channels, either directly or by altering SR Ca buffering, leading to spontaneous Ca release. To
test this, I plan to use both mouse and human pluripotent stem cell models. Recent studies have shown that
cardiomyocytes (CM) differentiated from human induced pluripotent stem cells (hiPSCs) can model CPVT and
be used to screen potential therapeutics. Utilizing the K180R mouse and hiPSC models I already generated, the
aims of this project are to determine how K180R affects SR calcium handling and to investigate how K180R
affects Casq2 Ca binding, localization, and polymerization. I will investigate how CMs are effected at the
physiological and cellular levels and determine how Casq2 is altered at the protein level. This project will provide
new insight into the role of Casq2 during the EC coupling cycle, the functional interaction between Casq2 and
RyR2, the termination of SR Ca release, and how Casq2 variants could lead to cardiac arrhythmias and/or heart
failure. This improved understanding of Casq2 could lead to better treatment strategies for patients suffering
from Casq2-dependent cardiac disorders.

## Key facts

- **NIH application ID:** 10087553
- **Project number:** 5F30HL145917-03
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Matthew J Wleklinski
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $48,294
- **Award type:** 5
- **Project period:** 2019-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10087553

## Citation

> US National Institutes of Health, RePORTER application 10087553, Cardiac Calsequestrin (Casq2) function in excitation-contraction coupling and cardiac arrhythmias (5F30HL145917-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10087553. Licensed CC0.

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