Disease-related cardiac troponins alter thin filament Ca2+ association and dissociation rates.
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.
Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio, United States of America.
Bin
B
Liu
Svetlana B
SB
Tikunova
Kristopher P
KP
Kline
Jalal K
JK
Siddiqui
Jonathan P
JP
Davis
D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D002318:Cardiovascular Diseases / Q000378:metabolism*; D002417:Cattle; D006801:Humans; D007700:Kinetics; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011817:Rabbits; D014336:Troponin / Q000378:metabolism*; D019209:Troponin C / Q000378:metabolism; D019210:Troponin I / Q000378:metabolism; D020107:Troponin T / Q000378:metabolism
D014336:Troponin; D019209:Troponin C; D019210:Troponin I; D020107:Troponin T; D002118:Calcium