The cardiac troponin C isoform and the length dependence of Ca2+ sensitivity of tension in myocardium.
The Ca2+ sensitivity of tension in cardiac muscle is length dependent, such that the sensitivity is diminished with decreasing sarcomere length below 2.4 microm. This length dependence of Ca2+ sensitivity of tension also forms the basis for the Frank-Starling mechanism in the heart. The fast-twitch skeletal muscle has a much lower length dependence of Ca2+ sensitivity. In a recent study of skinned cardiotrabeculae, we indicated that the exchange of endogenous cardiac troponin C (TnC) for skeletal troponin C also resulted in a major reduction in the length dependence to the level of skeletal muscle. These findings suggested that cardiac troponin C has a key role in the length-sensing mechanism. The present investigation supports this conclusion and delineates the specific domain in cardiac TnC responsible for the length effect. Chimeras splicing either 41, 61, or 96 N-terminal cardiac amino acids with the remaining skeletal residues have indicated that while Ca2+ binding in all three constructs is similar to that in wild type cardiac TnC, the functional responsiveness of the 96-cardiac residue construct is improved over the other two. This 96-cardiac residue construct yielded a tension response indistinguishable from that of wild-type cardiac TnC. A tryptophan variant of the chimera indicated fluorescence characteristics indistinguishable from cardiac troponin C. The findings provide further support for the idea that cardiac troponin C in situ is modified in response to sarcomere length change and thereby participates in the Frank-Starling mechanism. Moreover, the study indicates that the tropinin C length-sensing attribute originates within the N-terminal domain constituted by these 96 residues.
Akella
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AB
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Su
H
H
Sonnenblick
E H
EH
Rao
V G
VG
Gulati
J
J
D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D006224:Cricetinae; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D011993:Recombinant Fusion Proteins / Q000378:metabolism*; D012518:Sarcomeres / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D013050:Spectrometry, Fluorescence; D019209:Troponin C / Q000378:metabolism*; D014364:Tryptophan / Q000235:genetics
D011993:Recombinant Fusion Proteins; D019209:Troponin C; D014364:Tryptophan; D002118:Calcium