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

Background-a highly organized transverse tubule (t-tubule) network is necessary for efficient ca2+-induced ca2+ 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 ca2+ handling that culminated in heart failure compared with wild-type mice. activation of gαq/phospholipase cb signaling increased the activity of the ca2+-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 ca2+ 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,ca2+ handling dysfunction,and progression to heart failure in this mouse model. © 2014 the authors.