# Novel Functions of the E-C Coupling Structural Protein Junctophilin-2 in the Heart

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2020 · $605,348

## Abstract

PROJECT SUMMARY
Junctophilin 2 (JP2) is an essential structural protein required for the formation of junctional couplings (i.e.,
cardiac dyads) between the transverse (T)-tubule membrane and the sarcoplasmic reticulum (SR). JP2 function
is therefore fundamental for the local control of Ca2+-induced Ca2+ release and efficient contraction in ventricular
myocytes during cardiac excitation-contraction (E-C) coupling. JP2 protein levels progressively decline in failing
human hearts and in animal models of heart failure leading to T-tubule remodeling and loss of E-C coupling
function. The downregulation of JP2 at E-C coupling sites is in part due to specific cleavage by the Ca2+-activated
protease calpain that is implicated in a variety of heart diseases. During the previous funding period, we
demonstrated that stress- and calpain-dependent cleavage of JP2 liberates a novel, nuclear translocating, N-
terminal fragment (JP2NT) that represses maladaptive transcriptional reprogramming in diseased hearts, thus
transducing E-C uncoupling information into a unique cardio-protective excitation-transcription (E-T) coupling
signal to the nucleus. However, how JP2-mediated E-C and E-T coupling phenomena are mechanistically regulated
remains to be determined. Our new preliminary results show that JP2 is reproducibly phosphorylated in stressed
hearts near regions responsible for JP2 cleavage and the subcellular localization of JP2NT. In this competitive
renewal application, we aim to define how stress-induced post-translational modifications regulate the structure,
localization, and function of JP2/JP2NT. We hypothesize that JP2NT-mediated E-T coupling is tightly regulated
by cardiac stress-dependent phosphorylation of JP2 that determines JP2 sensitivity to calpain and JP2NT
nuclear translocation and transcriptional activity. To test our hypothesis, in Aim 1, we will use mutation analysis
and cell models to determine how JP2 phosphorylation regulates E-C coupling and cleavage-induced JP2NT
generation, nuclear translocation and transcriptional regulation. In Aim 2, we will utilize our novel JP2 calpain
resistant mice in combination with JP2NT overexpression to determine how these targeted approaches modulate
cardiac responses to stress in vivo. We will determine how E-C coupling structure/function and cardiac gene
transcription are altered in these mice in response to pressure overload and myocardial infarction. We expect
our studies will provide significant insights into the regulatory mechanisms governing JP2/JP2NT function and
their salutary contribution toward heart disease pathogenesis.

## Key facts

- **NIH application ID:** 10058735
- **Project number:** 2R01HL130346-05
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Long-Sheng Song
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $605,348
- **Award type:** 2
- **Project period:** 2016-01-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10058735

## Citation

> US National Institutes of Health, RePORTER application 10058735, Novel Functions of the E-C Coupling Structural Protein Junctophilin-2 in the Heart (2R01HL130346-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10058735. Licensed CC0.

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