title: 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.
  
  
  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: Department of Physiology and Biophysics and Institute of Molecular Cardiology, Stony Brook University, Stony Brook, NY (C.Y.C.W., Y.P.J., S.L., E.E., R.Z.L.).
authors: Chia-Yen C
authors: CY
authors: Wu
authors: Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA (B.C., L.S.S.).
authors: Biyi
authors: B
authors: Chen
authors: Department of Physiology and Biophysics and Institute of Molecular Cardiology, Stony Brook University, Stony Brook, NY (C.Y.C.W., Y.P.J., S.L., E.E., R.Z.L.).
authors: Ya-Ping
authors: YP
authors: Jiang
authors: Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY (Z.J., E.E.).
authors: Zhiheng
authors: Z
authors: Jia
authors: Department of Medicine and Proteomics Center, Stony Brook University, Stony Brook, NY (D.W.M.).
authors: Dwight W
authors: DW
authors: Martin
authors: Department of Physiology and Biophysics and Institute of Molecular Cardiology, Stony Brook University, Stony Brook, NY (C.Y.C.W., Y.P.J., S.L., E.E., R.Z.L.).
authors: Shengnan
authors: S
authors: Liu
authors: Department of Physiology and Biophysics and Institute of Molecular Cardiology, Stony Brook University, Stony Brook, NY (C.Y.C.W., Y.P.J., S.L., E.E., R.Z.L.) Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY (Z.J., E.E.).
authors: Emilia
authors: E
authors: Entcheva
authors: Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA (B.C., L.S.S.).
authors: Long-Sheng
authors: LS
authors: Song
authors: Department of Physiology and Biophysics and Institute of Molecular Cardiology, Stony Brook University, Stony Brook, NY (C.Y.C.W., Y.P.J., S.L., E.E., R.Z.L.) Department of Veterans Affairs Medical Center, Northport, NY (R.Z.L.).
authors: Richard Z
authors: RZ
authors: Lin
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000502:physiology*; D018563:Disease Notification; D015536:Down-Regulation / Q000502:physiology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000502:physiology; D006333:Heart Failure / Q000503:physiopathology*; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D032342:Muscle Cells / Q000502:physiology; D009124:Muscle Proteins / Q000378:metabolism / Q000502:physiology*; D059748:Proteolysis; D015398:Signal Transduction / Q000502:physiology
chemical_list: D002118:Calcium; D002154:Calpain; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D008565:Membrane Proteins; D009124:Muscle Proteins; C000589042:JP2 protein, mouse
keywords: Calpain; G protein; T‐tubules; heart failure; junctophilin‐2