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Arch Biochem Biophys. 2011 Nov;515(1-2):37-45. doi: 10.1016/j.abb.2011.08.013. Epub 2011 Sep 5.

Structure of the NH2-terminal variable region of cardiac troponin T determines its sensitivity to restrictive cleavage in pathophysiological adaptation.

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  • 1Section of Molecular Cardiology, Evanston Northwestern Healthcare, Northwestern University Feinberg School of Medicine, Evanston, IL 60201, USA.


We previously reported that the NH(2)-terminal variable region of cardiac troponin T (cTnT) is removed by restrictive μ-calpain cleavage in myocardial ischemia-reperfusion [24]. Selective removal of the NH(2)-terminal variable region of cTnT had a compensatory effect on myocardial contractility [25]. Here we further studied this posttranslational modification under pathophysiological conditions. Thrombin perfusion of isolated mouse hearts and cardiomyocytes induced the production of NH(2)-terminal truncated cTnT (cTnT-ND), suggesting a role of calcium overloading. Ouabain treatment of primary cultures of mouse cardiomyocytes in hypokalemic media, another calcium overloading condition, also produced cTnT-ND. Exploring the molecular mechanisms, we found that cTnT phosphorylation was primarily in the NH(2)-terminal region and the level of cTnT phosphorylation did not change under the calcium overloading conditions. However, alternatively spliced cTnT variants differing in the NH(2)-terminal primary structure produced significantly different levels of cTnT-ND in vivo in transgenic mouse hearts. The results suggest that stress conditions involving calcium overloading may convey an increased sensitivity of cTnT to the restrictive μ-calpain proteolysis, in which structure of the NH(2)-terminal variable region may play a determining role.

Copyright © 2011 Elsevier Inc. All rights reserved.

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