Interaction of the Joining Region in Junctophilin-2 With the L-Type Ca2+ Channel Is Pivotal for Cardiac Dyad Assembly and Intracellular Ca2+ Dynamics

被引：49

作者：

Gross, Polina ^{[1
]}

Johnson, Jaslyn ^{[1
]}

Romero, Carlos M. ^{[1
]}

Eaton, Deborah M. ^{[1
]}

Poulet, Claire ^{[3
]}

Sanchez-Alonso, Jose ^{[3
]}

Lucarelli, Carla ^{[3
,6
]}

Ross, Jean ^{[4
]}

Gibb, Andrew A. ^{[2
]}

Garbincius, Joanne F. ^{[2
]}

Lambert, Jonathan ^{[2
]}

Varol, Erdem ^{[5
]}

Yang, Yijun ^{[1
]}

Wallner, Markus ^{[1
,7
,8
]}

Feldsott, Eric A. ^{[1
]}

Kubo, Hajime ^{[1
]}

Berretta, Remus M. ^{[1
]}

Yu, Daohai ^{[9
]}

Rizzo, Victor ^{[1
]}

Elrod, John ^{[2
]}

Sabri, Abdelkarim ^{[1
]}

Gorelik, Julia ^{[3
]}

Chen, Xiongwen ^{[1
]}

Houser, Steven R. ^{[1
]}

机构：

[1] Lewis Katz Temple Univ, Sch Med, Dept Physiol, Cardiovasc Res Ctr, Philadelphia, PA USA

[2] Lewis Katz Temple Univ, Sch Med, Dept Pharmacol, Ctr Translat Med, Philadelphia, PA USA

[3] Imperial Coll London, NIHR Imperial Biomed Res Ctr, Natl Heart & Lung Inst, London, England

[4] Delaware Biotechnol Inst, Bioimaging Ctr Res, Newark, DE USA

[5] Columbia Univ, Dept Stat, Ctr Theoret Neurosci, New York, NY USA

[6] Univ Verona, Cardiovasc Sci, Verona, Italy

[7] Med Univ Graz, Div Cardiol, Graz, Austria

[8] CBmed GmbH, Ctr Biomarker Res Med, Graz, Austria

[9] Temple Univ, Dept Clin Sci, Lewis Katz Sch Med, Philadelphia, PA 19140 USA

来源：

CIRCULATION RESEARCH | 2021年 / 128卷 / 01期

基金：

美国国家卫生研究院;

关键词：

calcium channels; heart failure; junctophilin;

D O I：

10.1161/CIRCRESAHA.119.315715

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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-alpha 1C 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 Ca2+-release with impaired excitation-contraction coupling after beta-adrenergic stimulation. The disturbed Ca2+ 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 CICR in cardiomyocytes.

引用

页码：92 / 114

页数：23

共 97 条

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