title: Structure of the NH2-terminal variable region of cardiac troponin T determines its sensitivity to restrictive cleavage in pathophysiological adaptation.
abstract: 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.
authors.affiliation: Section of Molecular Cardiology, Evanston Northwestern Healthcare, Northwestern University Feinberg School of Medicine, Evanston, IL 60201, USA.
authors.forename: Zhiling
authors.initials: Z
authors.lastname: Zhang
authors.forename: Han-Zhong
authors.initials: HZ
authors.lastname: Feng
authors.forename: J-P
authors.initials: JP
authors.lastname: Jin
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D006868:Hydrolysis; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism*; D010766:Phosphorylation; D013312:Stress, Physiological; D020107:Troponin T / Q000737:chemistry / Q000378:metabolism*
chemical_list: D020107:Troponin T