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.
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.
|Chiang, David Y; Li, Na; Wang, Qiongling et al. (2014) Impaired local regulation of ryanodine receptor type 2 by protein phosphatase 1 promotes atrial fibrillation. Cardiovasc Res 103:178-87|
|Wang, Wei; Landstrom, Andrew P; Wang, Qiongling et al. (2014) Reduced junctional Na+/Ca2+-exchanger activity contributes to sarcoplasmic reticulum Ca2+ leak in junctophilin-2-deficient mice. Am J Physiol Heart Circ Physiol 307:H1317-26|
|Di Carlo, Mariano N; Said, Matilde; Ling, Haiyun et al. (2014) CaMKII-dependent phosphorylation of cardiac ryanodine receptors regulates cell death in cardiac ischemia/reperfusion injury. J Mol Cell Cardiol 74:274-83|
|Respress, Jonathan L; Gershovich, Pavel M; Wang, Tiannan et al. (2014) Long-term simulated microgravity causes cardiac RyR2 phosphorylation and arrhythmias in mice. Int J Cardiol 176:994-1000|
|Nabben, Miranda; van Bree, Bianca W J; Lenaers, Ellen et al. (2014) Lack of UCP3 does not affect skeletal muscle mitochondrial function under lipid-challenged conditions, but leads to sudden cardiac death. Basic Res Cardiol 109:447|
|Dobrev, Dobromir; Wehrens, Xander H T (2014) Role of RyR2 phosphorylation in heart failure and arrhythmias: Controversies around ryanodine receptor phosphorylation in cardiac disease. Circ Res 114:1311-9; discussion 1319|
|Chiang, David Y; Kongchan, Natee; Beavers, David L et al. (2014) Loss of microRNA-106b-25 cluster promotes atrial fibrillation by enhancing ryanodine receptor type-2 expression and calcium release. Circ Arrhythm Electrophysiol 7:1214-22|
|Landstrom, Andrew P; Beavers, David L; Wehrens, Xander H T (2014) The junctophilin family of proteins: from bench to bedside. Trends Mol Med 20:353-62|
|Giudice, Jimena; Xia, Zheng; Wang, Eric T et al. (2014) Alternative splicing regulates vesicular trafficking genes in cardiomyocytes during postnatal heart development. Nat Commun 5:3603|
|Li, Na; Chiang, David Y; Wang, Sufen et al. (2014) Ryanodine receptor-mediated calcium leak drives progressive development of an atrial fibrillation substrate in a transgenic mouse model. Circulation 129:1276-85|
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