Hypertrophic cardiomyopathy (HCM) is the most-common inherited form of heart disease, characterized by thickening of the left ventricular wall, contractile dysfunction, and potentially fatal arrhythmias. There is extensive evidence that defects in excitation-contraction coupling (ECC) contribute to the pathogenesis of both cardiomyopathy and arrhythmias. Specialized membrane junctions known as 'junctional membrane complexes'(JMC) are important subcellular structures in L-type Ca channels (LTCC) on the plasmalemma communicate with ryanodine receptors (RyR2) on the sarcoplasmic reticulum (SR) to initiate contraction. Little is known about the proteins that govern proper subcellular targeting of Ca channels within JMCs, but junctophilin-2 (JPH2) has been identified as a key candidate. In humans, missense mutations in JPH2 cause HCM, although the molecular mechanisms remain unresolved. We have recently demonstrated that JPH2 also binds to and modulates RyR2 channels in the JMC, but the exact protein domains involved in these interactions are still unknown. Moreover, reduced expression of JPH2 has been reported in patients with HCM and animal models of heart failure, but it is unclear whether loss of JPH2 is directly linked to impaired contractility and/or arrhythmias in failing hearts. We have generated several mouse models with HCM-linked JPH2 mutations or with increased/decreased JPH2 expression levels in the heart. The long-term goal of this project is to define the molecular mechanisms by which JPH2 and associated molecules regulate JMC integrity and EC coupling in normal hearts, and how aberrant JPH2 function causes HCM, heart failure, and arrhythmias. Our overall hypothesis is that in normal hearts JPH2 is required for JMC integrity and the regulation of Ca channels therein, whereas loss of JPH2 function due to downregulation or mutation causes cardiomyopathy, heart failure and arrhythmias. To test this hypothesis, we propose to:
In Aim 1, determine the role of JPH2 in organizing key Ca handling proteins within the JMC. - In Aim 2, unravel the mechanisms by which genetic JPH2 variants cause HCM. - In Aim 3, determine if JPH2 downregulation is the cause of loss of TTs/JMCs in heart failure.
The proposed work will study how junctophilin-2 (JPH2) regulates the formation of calcium release units and the fundamental process of excitation-contraction coupling in the heart. Moreover, we will study how JPH2 deficiency or inherited mutations in JPH2 cause cardiomyopathy and life-threatening cardiac arrhythmias.
|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|
|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|