Polina Gross1, Jaslyn Johnson1, Carlos M Romero1, Deborah M Eaton1, Claire Poulet2, Jose Sanchez-Alonso2, Carla Lucarelli2,3, Jean Ross4, Andrew A Gibb5, Joanne F Garbincius5, Jonathan Lambert5, Erdem Varol6, Yijun Yang1, Markus Wallner1,7,8, Eric A Feldsott1, Hajime Kubo1, Remus M Berretta1, Daohai Yu9, Victor Rizzo1, John Elrod5, Abdelkarim Sabri1, Julia Gorelik2, Xiongwen Chen1, Steven R Houser1. 1. Department of Physiology, Cardiovascular Research Center (P.G., J.J., C.M.R., D.M.E., Y.Y., M.W., E.A.F., H.K., R.M.B., V.R., A.S., X.C., S.R.H.), Lewis Katz Temple University School of Medicine, Philadelphia, PA. 2. NIHR Imperial Biomedical Research Centre, National Heart and Lung Institute, Imperial College London, London, United Kingdom (C.P., J.S.-A., C.L., J.G.). 3. Cardiovascular Science, University of Verona, Verona, Italy (C.L.). 4. Bioimaging Center Research, Delaware Biotechnology Institute, Newark, DE (J.R.). 5. Department of Pharmacology, Center for Translational Medicine (A.A.G., J.F.G., J.L., J.E.), Lewis Katz Temple University School of Medicine, Philadelphia, PA. 6. Department of Statistics, Center for Theoretical Neuroscience, Columbia University, New York, NY (E.V.). 7. Division of Cardiology, Medical University of Graz, Austria (M.W.). 8. Center for Biomarker Research in Medicine, CBmed GmbH, Graz, Austria (M.W.). 9. Department of Clinical Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA (D.Y.).
Abstract
RATIONALE: Ca2+-induced Ca2+ release (CICR) in normal hearts requires close approximation of L-type calcium channels (LTCCs) within the transverse tubules (T-tubules) and RyR (ryanodine receptors) within the junctional sarcoplasmic reticulum. CICR is disrupted in cardiac hypertrophy and heart failure, which is associated with loss of T-tubules and disruption of cardiac dyads. In these conditions, LTCCs are redistributed from the T-tubules to disrupt CICR. The molecular mechanism responsible for LTCCs recruitment to and from the T-tubules is not well known. JPH (junctophilin) 2 enables close association between T-tubules and the junctional sarcoplasmic reticulum to ensure efficient CICR. JPH2 has a so-called joining region that is located near domains that interact with T-tubular plasma membrane, where LTCCs are housed. The idea that this joining region directly interacts with LTCCs and contributes to LTCC recruitment to T-tubules is unknown. OBJECTIVE: To determine if the joining region in JPH2 recruits LTCCs to T-tubules through direct molecular interaction in cardiomyocytes to enable efficient CICR. METHODS AND RESULTS: Modified abundance of JPH2 and redistribution of LTCC were studied in left ventricular hypertrophy in vivo and in cultured adult feline and rat ventricular myocytes. Protein-protein interaction studies showed that the joining region in JPH2 interacts with LTCC-α1C subunit and causes LTCCs distribution to the dyads, where they colocalize with RyRs. A JPH2 with induced mutations in the joining region (mutPG1JPH2) caused T-tubule remodeling and dyad loss, showing that an interaction between LTCC and JPH2 is crucial for T-tubule stabilization. mutPG1JPH2 caused asynchronous Ca2+-release with impaired excitation-contraction coupling after β-adrenergic stimulation. The disturbed Ca2+ regulation in mutPG1JPH2 overexpressing myocytes caused calcium/calmodulin-dependent kinase II activation and altered myocyte bioenergetics. CONCLUSIONS: The interaction between LTCC and the joining region in JPH2 facilitates dyad assembly and maintains normal CICR in cardiomyocytes.
RATIONALE: Ca2+-induced Ca2+ release (CICR) in normal hearts requires close approximation of L-type calcium channels (LTCCs) within the transverse tubules (T-tubules) and RyR (ryanodine receptors) within the junctional sarcoplasmic reticulum. CICR is disrupted in cardiac hypertrophy and heart failure, which is associated with loss of T-tubules and disruption of cardiac dyads. In these conditions, LTCCs are redistributed from the T-tubules to disrupt CICR. The molecular mechanism responsible for LTCCs recruitment to and from the T-tubules is not well known. JPH (junctophilin) 2 enables close association between T-tubules and the junctional sarcoplasmic reticulum to ensure efficient CICR. JPH2 has a so-called joining region that is located near domains that interact with T-tubular plasma membrane, where LTCCs are housed. The idea that this joining region directly interacts with LTCCs and contributes to LTCC recruitment to T-tubules is unknown. OBJECTIVE: To determine if the joining region in JPH2 recruits LTCCs to T-tubules through direct molecular interaction in cardiomyocytes to enable efficient CICR. METHODS AND RESULTS: Modified abundance of JPH2 and redistribution of LTCC were studied in left ventricular hypertrophy in vivo and in cultured adult feline and rat ventricular myocytes. Protein-protein interaction studies showed that the joining region in JPH2 interacts with LTCC-α1C subunit and causes LTCCs distribution to the dyads, where they colocalize with RyRs. A JPH2 with induced mutations in the joining region (mutPG1JPH2) caused T-tubule remodeling and dyad loss, showing that an interaction between LTCC and JPH2 is crucial for T-tubule stabilization. mutPG1JPH2 caused asynchronous Ca2+-release with impaired excitation-contraction coupling after β-adrenergic stimulation. The disturbed Ca2+ regulation in mutPG1JPH2 overexpressing myocytes caused calcium/calmodulin-dependent kinase II activation and altered myocyte bioenergetics. CONCLUSIONS: The interaction between LTCC and the joining region in JPH2 facilitates dyad assembly and maintains normal CICR in cardiomyocytes.
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