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- Title
Disease-Related Cardiac Troponins Alter Thin Filament Ca<sup>2+</sup> Association and Dissociation Rates.
- Authors
Bin Liu; Tikunova, Svetlana B.; Kline, Kristopher P.; Siddiqui, Jalal K.; Davis, Jonathan P.
- Abstract
The contractile response of the heart can be altered by disease-related protein modifications to numerous contractile proteins. By utilizing an IAANS labeled fluorescent troponin C, TnCT53CIAANS, we examined the effects of ten disease-related troponin modifications on the Ca2+ binding properties of the troponin complex and the reconstituted thin filament. The selected modifications are associated with a broad range of cardiac diseases: three subtypes of familial cardiomyopathies (dilated, hypertrophic and restrictive) and ischemia-reperfusion injury. Consistent with previous studies, the majority of the protein modifications had no effect on the Ca2+ binding properties of the isolated troponin complex. However, when incorporated into the thin filament, dilated cardiomyopathy mutations desensitized (up to 3.3-fold), while hypertrophic and restrictive cardiomyopathy mutations, and ischemia-induced truncation of troponin I, sensitized the thin filament to Ca2+ (up to 6.3-fold). Kinetically, the dilated cardiomyopathy mutations increased the rate of Ca2+ dissociation from the thin filament (up to 2.5-fold), while the hypertrophic and restrictive cardiomyopathy mutations, and the ischemia-induced truncation of troponin I decreased the rate (up to 2-fold). The protein modifications also increased (up to 5.4-fold) or decreased (up to 2.5-fold) the apparent rate of Ca2+ association to the thin filament. Thus, the disease-related protein modifications alter Ca2+ binding by influencing both the association and dissociation rates of thin filament Ca2+ exchange. These alterations in Ca2+ exchange kinetics influenced the response of the thin filament to artificial Ca2+ transients generated in a stopped-flow apparatus. Troponin C may act as a hub, sensing physiological and pathological stimuli to modulate the Ca2+-binding properties of the thin filament and influence the contractile performance of the heart.
- Subjects
HEART diseases; PROTEINS; TROPONIN; MICROFILAMENT proteins; CARDIOMYOPATHIES
- Publication
PLoS ONE, 2012, Vol 7, Issue 6, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0038259