Interaction of the Joining Region in Junctophilin-2 With the L-Type Ca
| Autor: | Polina, Gross, Jaslyn, Johnson, Carlos M, Romero, Deborah M, Eaton, Claire, Poulet, Jose, Sanchez-Alonso, Carla, Lucarelli, Jean, Ross, Andrew A, Gibb, Joanne F, Garbincius, Jonathan, Lambert, Erdem, Varol, Yijun, Yang, Markus, Wallner, Eric A, Feldsott, Hajime, Kubo, Remus M, Berretta, Daohai, Yu, Victor, Rizzo, John, Elrod, Abdelkarim, Sabri, Julia, Gorelik, Xiongwen, Chen, Steven R, Houser |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Organelle Biogenesis Calcium Channels L-Type Membrane Proteins Muscle Proteins Ryanodine Receptor Calcium Release Channel Mitochondria Heart Article Rats Sprague-Dawley Disease Models Animal Kinetics Mutation cardiovascular system Cats Animals Humans Calcium Hypertrophy Left Ventricular Myocytes Cardiac Protein Interaction Domains and Motifs Calcium Signaling Calcium-Calmodulin-Dependent Protein Kinase Type 2 Cells Cultured Excitation Contraction Coupling Protein Binding |
| Zdroj: | Circ Res |
| ISSN: | 1524-4571 |
| Popis: | RATIONALE: Ca(2+) induced Ca(2+) release (CICR) in normal hearts requires close approximation of L-type calcium channels (LTCCs) within the transverse tubules (T-tubules), and Ryanodine receptors (RyR) within the junctional sarcoplasmic reticulum (jSR). 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. Junctophilin-2 (JPH2) enables close association between T-tubules and the jSR 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 (mut(PG1)JPH2) caused T-tubule remodeling and dyad loss, showing that an interaction between LTCC and JPH2 is crucial for T-tubule stabilization. mut(PG1)JPH2 caused asynchronous Ca(2+)-release with impaired excitation-contraction (EC) coupling after β-adrenergic stimulation. The disturbed Ca(2+) regulation in mut(PG1)JPH2 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 CIRC in cardiomyocytes. |
| Databáze: | OpenAIRE |
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