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.

Public Health Relevance

Current treatments of heart failure continue to be insufficient for all patients. This project aims to determine how a recently identified pathway in the heart protects itself from pathological stresses. This research will provide fundamental insights into how this pathway can be leveraged to improve cardiovascular health.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
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Tjurmina, Olga A
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University of Iowa
Internal Medicine/Medicine
Schools of Medicine
Iowa City
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Guo, Ang; Chen, Rong; Wang, Yihui et al. (2018) Transient activation of PKC results in long-lasting detrimental effects on systolic [Ca2+]i in cardiomyocytes by altering actin cytoskeletal dynamics and T-tubule integrity. J Mol Cell Cardiol 115:104-114
Chiamvimonvat, Nipavan; Song, Long-Sheng (2018) LRRC10 (Leucine-Rich Repeat Containing Protein 10) and REEP5 (Receptor Accessory Protein 5) as Novel Regulators of Cardiac Excitation-Contraction Coupling Structure and Function. J Am Heart Assoc 7:
Guo, Ang; Wang, Yihui; Chen, Biyi et al. (2018) E-C coupling structural protein junctophilin-2 encodes a stress-adaptive transcription regulator. Science 362:
Wang, Yihui; Chen, Biyi; Huang, Chun-Kai et al. (2018) Targeting Calpain for Heart Failure Therapy: Implications From Multiple Murine Models. JACC Basic Transl Sci 3:503-517
Yan, Jiajie; Zhao, Weiwei; Thomson, Justin K et al. (2018) Stress Signaling JNK2 Crosstalk With CaMKII Underlies Enhanced Atrial Arrhythmogenesis. Circ Res 122:821-835
Liu, Wenjuan; Deng, Jianxin; Ding, Wenwen et al. (2017) Decreased KCNE2 Expression Participates in the Development of Cardiac Hypertrophy by Regulation of Calcineurin-NFAT (Nuclear Factor of Activated T Cells) and Mitogen-Activated Protein Kinase Pathways. Circ Heart Fail 10:
Zhang, Caimei; Chen, Biyi; Wang, Yihui et al. (2017) MG53 is dispensable for T-tubule maturation but critical for maintaining T-tubule integrity following cardiac stress. J Mol Cell Cardiol 112:123-130
Arora, Rishi; Aistrup, Gary L; Supple, Stephen et al. (2017) Regional distribution of T-tubule density in left and right atria in dogs. Heart Rhythm 14:273-281
Hall, Duane D; Ponce, Jessica M; Chen, Biyi et al. (2017) Ectopic expression of Cdk8 induces eccentric hypertrophy and heart failure. JCI Insight 2:
Guo, Yuxuan; VanDusen, Nathan J; Zhang, Lina et al. (2017) Analysis of Cardiac Myocyte Maturation Using CASAAV, a Platform for Rapid Dissection of Cardiac Myocyte Gene Function In Vivo. Circ Res 120:1874-1888

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