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)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-CVRS-K (02))
Program Officer
Lathrop, David A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Baylor College of Medicine
Schools of Medicine
United States
Zip Code
Quick, Ann P; Wang, Qiongling; Philippen, Leonne E et al. (2016) Striated Muscle Preferentially Expressed Protein Kinase (SPEG) Is Essential for Cardiac Function by Regulating Junctional Membrane Complex Activity. Circ Res :
Li, Na; Dobrev, Dobromir; Wehrens, Xander H T (2016) PITX2: a master regulator of cardiac channelopathy in atrial fibrillation? Cardiovasc Res 109:345-7
Nutter, Curtis A; Jaworski, Elizabeth A; Verma, Sunil K et al. (2016) Dysregulation of RBFOX2 Is an Early Event in Cardiac Pathogenesis of Diabetes. Cell Rep 15:2200-13
Uchinoumi, Hitoshi; Yang, Yi; Oda, Tetsuro et al. (2016) CaMKII-dependent phosphorylation of RyR2 promotes targetable pathological RyR2 conformational shift. J Mol Cell Cardiol 98:62-72
Heijman, Jordi; Algalarrondo, Vincent; Voigt, Niels et al. (2016) The value of basic research insights into atrial fibrillation mechanisms as a guide to therapeutic innovation: a critical analysis. Cardiovasc Res 109:467-79
Reynolds, Julia O; Quick, Ann P; Wang, Qiongling et al. (2016) Junctophilin-2 gene therapy rescues heart failure by normalizing RyR2-mediated Ca(2+) release. Int J Cardiol 225:371-380
Wu, Yuejin; Valdivia, Héctor H; Wehrens, Xander H T et al. (2016) A Single Protein Kinase A or Calmodulin Kinase II Site Does Not Control the Cardiac Pacemaker Ca2+ Clock. Circ Arrhythm Electrophysiol 9:e003180
Herrera, José A; Ward, Christopher S; Wehrens, Xander H T et al. (2016) Methyl-CpG binding-protein 2 function in cholinergic neurons mediates cardiac arrhythmogenesis. Hum Mol Genet :
Chiang, David Y; Heck, Albert J R; Dobrev, Dobromir et al. (2016) Regulating the regulator: Insights into the cardiac protein phosphatase 1 interactome. J Mol Cell Cardiol 101:165-172
Schulte, J S; Fehrmann, E; Tekook, M A et al. (2016) Cardiac expression of the CREM repressor isoform CREM-IbΔC-X in mice leads to arrhythmogenic alterations in ventricular cardiomyocytes. Basic Res Cardiol 111:15

Showing the most recent 10 out of 105 publications