| First Author | Guo A | Year | 2015 |
| Journal | J Biol Chem | Volume | 290 |
| Issue | 29 | Pages | 17946-55 |
| PubMed ID | 26063807 | Mgi Jnum | J:223756 |
| Mgi Id | MGI:5660160 | Doi | 10.1074/jbc.M115.652396 |
| Citation | Guo A, et al. (2015) Molecular Determinants of Calpain-dependent Cleavage of Junctophilin-2 Protein in Cardiomyocytes. J Biol Chem 290(29):17946-55 |
| abstractText | Junctophilin-2 (JP2), a membrane-binding protein that provides a structural bridge between the plasmalemma and sarcoplasmic reticulum, is essential for precise Ca(2+)-induced Ca(2+) release during excitation-contraction coupling in cardiomyocytes. In animal and human failing hearts, expression of JP2 is decreased markedly, but the molecular mechanisms underlying JP2 down-regulation remain incompletely defined. In mouse hearts, ischemia/reperfusion injury resulted in acute JP2 down-regulation, which was attenuated by pretreatment with the calpain inhibitor MDL-28170 or by transgenic overexpression of calpastatin, an endogenous calpain inhibitor. Using a combination of computational analysis to predict calpain cleavage sites and in vitro calpain proteolysis reactions, we identified four putative calpain cleavage sites within JP2 with three N-terminal and one C-terminal cleavage sites. Mutagenesis defined the C-terminal region of JP2 as the predominant calpain cleavage site. Exogenous expression of putative JP2 cleavage fragments was not sufficient to rescue Ca(2+) handling in JP2-deficient cardiomyocytes, indicating that cleaved JP2 is non-functional for normal Ca(2+)-induced Ca(2+) release. These data provide new molecular insights into the posttranslational regulatory mechanisms of JP2 in cardiac diseases. |
