It is well established that altered sarcoplasmic reticulum (SR) Ca handling plays a key role in HF pathogenesis. Whereas altered post-translational modifications (PTM) of the SR Ca release channel/ ryanodine receptor type- 2 (RyR2) have been linked to HF development, it remains highly controversial which kinases and phosphatases underlie these disease-associated changes. RyR2 hyper-phosphorylation can be caused by increased activity of protein kinase A (PKA) and Ca/calmodulin-dependent protein kinase II (CaMKII). However, there remains significant controversy about the mechanisms underlying altered phosphorylation of RyR2 in HF. We have identified a novel kinase within the RyR2 macromolecular complex, known as `striated muscle preferentially expressed gene' (SPEG). Our preliminary data show that SPEG phosphorylates a novel phosphorylation site on RyR2, S2811. In addition, our data suggest that SPEG levels are downregulated in patients and mice with congestive heart failure. Our long-term goal is to define the molecular and cellular mechanisms by which SEPG regulates RyR2 and intracellular Ca handling in normal and failing hearts. The overall hypothesis is that SPEG phosphorylates a novel S2811 residue on RyR2, which modulates RyR2 activity and intracellular Ca handling in cardiac myocytes.
Specific aim (1) will determine how SPEG binds to RyR2 and how SPEG modifies intracellular Ca handling.
Specific aim (2) will assess the role of SPEG modulation of RyR2 in heart failure.
Specific aim (3) will determine the role of SPEG-mediated phosphorylation of S2811 on RyR2 in normal and failing hearts. Significance: Heart failure (HF) is a deadly and costly disease affecting 5.7 millin people in the US alone, and a leading cause of hospitalization for those >65 years of age. A better understanding of the molecular mechanisms underlying abnormal RyR2 function in HF could lead to new pharmacological strategies.

Public Health Relevance

We will study how ryanodine receptors are regulated by the kinase `striated muscle preferentially expressed gene' (SPEG), and how this will affect intracellular calcium handling in healthy and failing hearts. This work is very significant because the molecular mechanisms of heart failure, one of the most common causes of death in the US, remain poorly understood.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL091947-08
Application #
9649234
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Adhikari, Bishow B
Project Start
2008-04-01
Project End
2021-02-28
Budget Start
2019-03-01
Budget End
2021-02-28
Support Year
8
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Physiology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Chiang, David Y; Alsina, Katherina M; Corradini, Eleonora et al. (2018) Rearrangement of the Protein Phosphatase 1 Interactome During Heart Failure Progression. Circulation 138:1569-1581
Klipp, Robert C; Li, Na; Wang, Qiongling et al. (2018) EL20, a potent antiarrhythmic compound, selectively inhibits calmodulin-deficient ryanodine receptor type 2. Heart Rhythm 15:578-586
Pan, Xiaolu; Philippen, Leonne; Lahiri, Satadru K et al. (2018) In Vivo Ryr2 Editing Corrects Catecholaminergic Polymorphic Ventricular Tachycardia. Circ Res 123:953-963
Lezcano, N; Mariángelo, J I E; Vittone, L et al. (2018) Early effects of Epac depend on the fine-tuning of the sarcoplasmic reticulum Ca2+ handling in cardiomyocytes. J Mol Cell Cardiol 114:1-9
Yao, Chunxia; Veleva, Tina; Scott Jr, Larry et al. (2018) Enhanced Cardiomyocyte NLRP3 Inflammasome Signaling Promotes Atrial Fibrillation. Circulation 138:2227-2242
Ni, Li; Scott Jr, Larry; Campbell, Hannah M et al. (2018) Atrial-Specific Gene Delivery Using an Adeno-Associated Viral Vector. Circ Res :
Auguste, Gaelle; Gurha, Priyatansh; Lombardi, Raffaella et al. (2018) Suppression of Activated FOXO Transcription Factors in the Heart Prolongs Survival in a Mouse Model of Laminopathies. Circ Res 122:678-692
Dobrev, Dobromir; Wehrens, Xander H T (2018) Mouse Models of Cardiac Arrhythmias. Circ Res 123:332-334
Wang, Qiongling; Quick, Ann P; Cao, Shuyi et al. (2018) Oxidized CaMKII (Ca2+/Calmodulin-Dependent Protein Kinase II) Is Essential for Ventricular Arrhythmia in a Mouse Model of Duchenne Muscular Dystrophy. Circ Arrhythm Electrophysiol 11:e005682
Wehrens, Xander H T (2018) Unraveling the Mechanisms by Which Calpain Inhibition Prevents Heart Failure Development. JACC Basic Transl Sci 3:518-520

Showing the most recent 10 out of 119 publications