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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Boineau, Robin
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
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
Quick, Ann P; Landstrom, Andrew P; Wehrens, Xander H T (2016) Junctophilin-2 at the intersection of arrhythmia and pathologic cardiac remodeling. Heart Rhythm 13:753-4
Yang, Pei-Chi; Moreno, Jonathan D; Miyake, Christina Y et al. (2016) In silico prediction of drug therapy in catecholaminergic polymorphic ventricular tachycardia. J Physiol 594:567-93
Bal, Naresh C; Maurya, Santosh K; Singh, Sushant et al. (2016) Increased Reliance on Muscle-based Thermogenesis upon Acute Minimization of Brown Adipose Tissue Function. J Biol Chem 291:17247-57
Aiba, Isamu; Wehrens, Xander H T; Noebels, Jeffrey L (2016) Leaky RyR2 channels unleash a brainstem spreading depolarization mechanism of sudden cardiac death. Proc Natl Acad Sci U S A 113:E4895-903
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

Showing the most recent 10 out of 68 publications