Defects in the regulation of intracellular Ca2+ released from sarcoplasmic reticulum (SR) stores have been demonstrated in inherited arrhythmia syndromes such as catecholaminergic polymorphic ventricular tachycardia (CPVT), but may also provide an arrhythmogenic trigger in acquired arrhythmias like atrial fibrillation (AF). Recent studies have revealed defects in the regulation of ryanodine receptor (RyR2) Ca2+ release channels in patients with AF. AF is the most prevalent arrhythmia, affecting more than 2 million Americans each year and causing a twofold increase in mortality. Since the activity of RyR2 is strongly regulated by Ca2+/calmodulin-dependent kinase (CaMKII), which binds to RyR2 and is activated in response to faster heart rates, it has been proposed that abnormal CaMKII regulation plays/a role in the onset of AF. The long-term goal of this project is to define the cellular/ molecular mechanisms by which abnormal CaMKII phosphorylation of RyR2 at serine 2814 (S2814) leads to AF, by studying human atrial biopsies and genetically-altered mice in which RyR2 activity has been altered, or the CaMKII phosphorylation site on RyR2 has been inactivated. Our hypothesis is that direct binding of CaMKII to RyR2 enables the enzyme to sense and amplify SR Ca2+ leak, which may increase the likelihood of AF in hearts more susceptible to arrhythmias due to an inherited mutation in RyR2 (R176Q) or the absence of the RyR2- stabilizing subunit FKBP12.6.
The specific aims are to: 1) Demonstrate that CaMKII phosphorylation at S2814 of RyR2 is increased in human atrial biopsies from patients with AF;2) Define the molecular mechanisms by which CaMKII regulates RyR2;3) Determine if CaMKII phosphorylation of RyR2 increases the probability of AF in RyR2-R176Q mutant or FKBP12.6-deficient mice;4) Determine if prevention of CaMKII phosphorylation of RyR2 in FKBP12.6-deficient mice decreases susceptibility to AF. We propose to conduct translational studies ranging from single channel measurements of RyR2, Ca2+ imaging in isolated cardiomyocytes and arrhythmia-inducibility studies in genetically-altered mice, to elucidate the molecular mechanisms underlying RyR2-dependent initiation of AF. It is anticipated that the results of these studies will advance our understanding of CaMKII-dependent mechanisms underlying the initiation of AF as well as other cardiac arrhythmias associated with abnormal Ca2+ homeostasis. Furthermore, the reagents and animal models developed for this project may be utilized to create new drugs for AF and other common diseases of the heart.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL089598-04
Application #
7860581
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Przywara, Dennis
Project Start
2007-08-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
4
Fiscal Year
2010
Total Cost
$438,500
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
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

Showing the most recent 10 out of 122 publications