Disease-Related Cardiac Troponins Alter Thin Filament Ca2+ Association and Dissociation Rates

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, [Formula: see text], we examined the effects of ten disease-related troponin modifications on the Ca(2+) 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 Ca(2+) 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 Ca(2+) (up to 6.3-fold). Kinetically, the dilated cardiomyopathy mutations increased the rate of Ca(2+) 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 Ca(2+) association to the thin filament. Thus, the disease-related protein modifications alter Ca(2+) binding by influencing both the association and dissociation rates of thin filament Ca(2+) exchange. These alterations in Ca(2+) exchange kinetics influenced the response of the thin filament to artificial Ca(2+) transients generated in a stopped-flow apparatus. Troponin C may act as a hub, sensing physiological and pathological stimuli to modulate the Ca(2+)-binding properties of the thin filament and influence the contractile performance of the heart.

DOI: 10.1371/journal.pone.0038259

Extracted Key Phrases

9 Figures and Tables

0102030201220132014201520162017
Citations per Year

59 Citations

Semantic Scholar estimates that this publication has 59 citations based on the available data.

See our FAQ for additional information.

Cite this paper

@inproceedings{Liu2012DiseaseRelatedCT, title={Disease-Related Cardiac Troponins Alter Thin Filament Ca2+ Association and Dissociation Rates}, author={Bin Liu and Svetlana B. Tikunova and Kristopher P. Kline and Jalal K. Siddiqui and Jonathan P . Davis}, booktitle={PloS one}, year={2012} }