Calpain-dependent cleavage of junctophilin-2 and T-tubule remodeling in a mouse model of reversible heart failure.

Abstract

BACKGROUND:

A highly organized transverse tubule (T-tubule) network is necessary for efficient Ca(2+)-induced Ca(2+) release and synchronized contraction of ventricular myocytes. Increasing evidence suggests that T-tubule remodeling due to junctophilin-2 (JP-2) downregulation plays a critical role in the progression of heart failure. However, the mechanisms underlying JP-2 dysregulation remain incompletely understood.

METHODS AND RESULTS:

A mouse model of reversible heart failure that is driven by conditional activation of the heterotrimeric G protein Gαq in cardiac myocytes was used in this study. Mice with activated Gαq exhibited disruption of the T-tubule network and defects in Ca(2+) handling that culminated in heart failure compared with wild-type mice. Activation of Gαq/phospholipase Cβ signaling increased the activity of the Ca(2+)-dependent protease calpain, leading to the proteolytic cleavage of JP-2. A novel calpain cleavage fragment of JP-2 is detected only in hearts with constitutive Gαq signaling to phospholipase Cβ. Termination of the Gαq signal was followed by normalization of the JP-2 protein level, repair of the T-tubule network, improvements in Ca(2+) handling, and reversal of heart failure. Treatment of mice with a calpain inhibitor prevented Gαq-dependent JP-2 cleavage, T-tubule disruption, and the development of heart failure.

CONCLUSIONS:

Disruption of the T-tubule network in heart failure is a reversible process. Gαq-dependent activation of calpain and subsequent proteolysis of JP-2 appear to be the molecular mechanism that leads to T-tubule remodeling, Ca(2+) handling dysfunction, and progression to heart failure in this mouse model.

• Authors: Chia-Yen C Wu, Biyi Chen, Ya-Ping Jiang, Zhiheng Jia, Dwight W Martin, Shengnan Liu, Emilia Entcheva, Long-Sheng Song, Richard Z Lin
• Journal: Journal of the American Heart Association (J Am Heart Assoc) Vol. 3 Issue 3 Pg. e000527 (Jun 23 2014) ISSN: 2047-9980 [Electronic] England
• PMID: 24958777 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Chemical References

• Membrane Proteins
• Muscle Proteins
• junctophilin-2 protein, mouse
• Calpain
• GTP-Binding Protein alpha Subunits, Gq-G11
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Calpain (physiology)
• Disease Notification
• Down-Regulation (physiology)
• GTP-Binding Protein alpha Subunits, Gq-G11 (physiology)
• Heart Failure (physiopathology)
• Membrane Proteins (metabolism, physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Muscle Cells (physiology)
• Muscle Proteins (metabolism, physiology)
• Proteolysis
• Signal Transduction (physiology)