# The Role of Junctophilin Type 2 in Cardiac Node Automaticity

> **NIH NIH K08** · DUKE UNIVERSITY · 2020 · $153,862

## Abstract

ABSTRACT
Diseases of the nodal tissue of the heart can be life threatening, particularly in the young. Nodal tissue
spontaneously depolarizes serving as a pacemaker for cardiac contraction, yet despite this central role
critical for survival, the cause of nodal dysfunction is poorly understood. This lack of mechanistic
understanding has impaired development of efficacious and selective pharmacotherapies, and as a
correlate, drugs levied against nodal disease carry significant toxicity for the patient and can still be
entirely ineffective. While the nodal automaticity was traditionally thought to be controlled by ion
channels on the plasma membrane, there is a growing body of evidence that calcium-signaling within the
cell may regulate spontaneous depolarization – its automaticity. Previous investigation has shown that
calcium leak from the internal calcium release channel, RyR2, may be associated with increased nodal
firing, thus understanding this so-called “calcium clock” can provide additional molecular targets for
nodal-specific novel therapeutics. I have created a mouse model of nodal-specific expression silencing
of a protein called junctophilin-2 (JPH2), which I have previously shown to be critical to effective calcium-
handling in the contractile myocyte, as a tool for studying a dysfunctional calcium clock. I have found
that this mouse has an elevated heart rate at rest and a rapidly firing atrioventricular node which causes
an arrhythmia known as accelerated junctional rhythm (AJR). I propose 3 specific aims to test our
central hypothesis that reduced JPH2 expression results in CaMKII-mediated increase in RyR2 gating
which causes increased store calcium leak and drives increased nodal automaticity and AJR. My aims
are to 1) utilize confocal-based calcium imaging of isolated nodal cells from HCN4:shJPH2 mice, coupled
with RyR2 single channel recordings to determine whether reduced JPH2 expression causes increased
calcium leak with higher RyR2 channel opening probability; 2) apply known chemical inhibitors of RyR2
to isolated single cells and HCN4:shJPh2 mice to assess whether calcium leak can be normalized and
AJR effectively treated; and 3) conduct biochemistry from isolated nodal tissue to determine the role of
CaMKII signaling, including its downstream phosphorylation targets, in regulation of nodal firing. I expect
that completion of these aims will yield clinically translatable mechanistic insight into the “calcium clock”
of the node. Through exploration of the first murine model of isolated cardiac nodal disease in the
literature, these aims will provide a substrate from which to test novel therapeutic agents specifically
targeted at perturbed calcium-signaling in nodal tissue. Completion of this 5-year training grant will allow
me to combine my clinical training in pediatric electrophysiology with exploration of the molecular
mechanisms of nodal disease and become an independently funded physician-scientist committed to
helping ch...

## Key facts

- **NIH application ID:** 9939631
- **Project number:** 5K08HL136839-05
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Andrew P. Landstrom
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $153,862
- **Award type:** 5
- **Project period:** 2018-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9939631

## Citation

> US National Institutes of Health, RePORTER application 9939631, The Role of Junctophilin Type 2 in Cardiac Node Automaticity (5K08HL136839-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9939631. Licensed CC0.

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