Cardiac ryanodine receptors (RyR2) play a central role in the process of excitation-contraction coupling in the heart. Alterations in RyR2 regulation are evident in a variety of cardiovascular diseases. Changes in the phosphorylation status of RyR2 have been described in patients with atrial fibrillation (AF), but the underlying abnormal mechanisms remain poorly understood. Considerable evidence suggests that RyR2 channels comprise a macromolecular complex with regulatory subunits including protein kinases and phosphatases. Studies in human atrial tissue and myocytes as well as experiments in knock-in mouse models have revealed that increased RyR2 phosphorylation predisposes to atrial ectopy and progression of AF. Our preliminary data suggest that alterations in the RyR2-bound protein phosphatases (PPs) might underlie elevated RyR2 phosphorylation in AF, although very little is currently known about this. The long-term goal of this project is to define the cellular/molecular mechanisms by which PPs regulate RyR2 activity in both normal hearts and in humans/mice with AF. The present proposal will test the general hypothesis that variation in levels of PP regulatory subunits associated with RyR2 contributes to enhanced sarcoplasmic reticulum (SR) Ca leak and vulnerability to AF.
Specific aim (1) will use biochemical and genetic approaches to dissect the role of PPs in the regulation of RyR2 phosphorylation.
Specific aim (2) will examine the effects of PP regulation of RyR2 on SR Ca handling in atrial cells using genetic mouse models.
Specific aim (3) will determine the role of PP regulation of RyR2 in atrial fibrillation in vivo in mouse models. Significance: Abnormal RyR2-mediated SR Ca leak has been associated with increased propensity to AF, the most prevalent type of cardiac arrhythmia. The mechanisms will be studied at the molecular, cellular and in vivo level, using recombinant proteins, genetic mouse models and human atrial biopsies. It is anticipated that these multidisciplinary studies will provide fundamental and new insights into the molecular mechanisms by which the RyR2 calcium release channel becomes dysregulated in AF. These insights may guide future developments of anti-arrhythmic drugs for the treatment of AF.

Public Health Relevance

The proposed work will study how the intracellular calcium release channel/ ryanodine receptor is regulated by protein phosphatases in the heart. Moreover, we will study how defective phosphatase regulation of these channels contributes to atrial fibrillation, the most common sustained cardiac arrhythmia in the US.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CVRS-K (02))
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Lathrop, David A
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Baylor College of Medicine
Schools of Medicine
United States
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Federico, Marilen; Portiansky, Enrique L; Sommese, Leandro et al. (2017) Calcium-calmodulin-dependent protein kinase mediates the intracellular signalling pathways of cardiac apoptosis in mice with impaired glucose tolerance. J Physiol 595:4089-4108
Quick, Ann P; Wang, Qiongling; Philippen, Leonne E et al. (2017) SPEG (Striated Muscle Preferentially Expressed Protein Kinase) Is Essential for Cardiac Function by Regulating Junctional Membrane Complex Activity. Circ Res 120:110-119
Quick, Ann P; Landstrom, Andrew P; Wang, Qiongling et al. (2017) Novel junctophilin-2 mutation A405S is associated with basal septal hypertrophy and diastolic dysfunction. JACC Basic Transl Sci 2:56-67
Klipp, Robert C; Li, Na; Wang, Qiongling et al. (2017) EL20, a potent antiarrhythmic compound, selectively inhibits calmodulin-deficient ryanodine receptor type 2. Heart Rhythm :
Li, Na; Wang, Qiongling; Sibrian-Vazquez, Martha et al. (2017) Treatment of catecholaminergic polymorphic ventricular tachycardia in mice using novel RyR2-modifying drugs. Int J Cardiol 227:668-673
Lezcano, N; Mariángelo, J I E; Vittone, L et al. (2017) Early effects of Epac depend on the fine-tuning of the sarcoplasmic reticulum Ca2+ handling in cardiomyocytes. J Mol Cell Cardiol 114:1-9
Heijman, Jordi; Ghezelbash, Shokoufeh; Wehrens, Xander H T et al. (2017) Serine/Threonine Phosphatases in Atrial Fibrillation. J Mol Cell Cardiol 103:110-120
Liu, Ruya; Lee, Jeongkyung; Kim, Byung S et al. (2017) Tead1 is required for maintaining adult cardiomyocyte function, and its loss results in lethal dilated cardiomyopathy. JCI Insight 2:
Pham, Khanh; Dong, Jie; Jiang, Xiqian et al. (2017) Loss of glutaredoxin 3 impedes mammary lobuloalveolar development during pregnancy and lactation. Am J Physiol Endocrinol Metab 312:E136-E149
Landstrom, Andrew P; Dobrev, Dobromir; Wehrens, Xander H T (2017) Calcium Signaling and Cardiac Arrhythmias. Circ Res 120:1969-1993

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