Biology of the troponin complex in cardiac myocytes
Section snippets
Anatomy of the sarcomere
The anatomy and organization of the cardiac myofibrillar apparatus provides the foundation for understanding the molecular basis of cardiac contractility. Genes encoding cardiac-restricted myofibrillar isoforms have evolved to regulate the unique contractile properties of the heart. The functional unit of the cardiac myocyte is the sarcomere.31 Each sarcomere is composed of a precise geometric arrangement of myosin-containing thick filaments surrounded by a hexagonal array of thin filaments
Molecular interactions among proteins in the troponin complex and the pressure-volume relation of the heart
The relation between left ventricular pressure and left ventricular volume during a heart beat serves as a useful framework to discuss functional correlates of the molecular signaling in the troponin complex and their role as a determinant of the inotropic state of the heart.46 Figure 4 illustrates pressure-volume (P-V) loops of the left ventricle determined during a basal state and following β-adrenergic stimulation. The P-V loops are rooted in the length-tension properties of the sarcomeres
A role for troponin in the Frank-Starling relation
There is substantial evidence that the cellular basis for the Frank-Starling relation, which is rooted in the length-tension relation of the sarcomere, involves an effect of sarcomere length on Ca2+ activation.50 That is, increases in sarcomere length not only increase maximum tension, but also increase myofilament Ca2+ sensitivity. In hearts, where myofilaments operate at submaximal levels of Ca2+ activation, length dependent alterations in Ca2+ sensitivity would be expected to be a major
Expression of troponin isoforms in the heart
The contractile properties of the heart are ultimately attributable to the expression of genes encoding cardiac-restricted myofibrillar protein isoforms. Expression of these gene products is precisely regulated during development and in response to myocardial injury and hemodynamic stress. The cTnC gene encodes a 160-amino acid polypeptide that is 70% identical to the fast skeletal troponin C (sTnC) protein isoform.16, 63 Despite the relatively high degree of sequence conservation, three
Transcriptional control of troponin gene expression: Insights into the molecular basis of cardiac myocyte differentiation and cardiac hypertrophy
Because of its cardiac-restricted pattern of expression, the cTnC gene has been utilized as a model system to elucidate the molecular mechanisms underlying cardiac myocyte-specific transcription and cardiac myocyte differentiation.16, 63, 78, 79, 80, 81, 82, 83, 84 The 124-bp murine cTnC promoter and 308-bp intragenic transcriptional enhancer restricts transgene expression to cardiac myocytes and embryonic skeletal muscle cells (the myotomal component of the somites); a pattern of gene
Troponins and stunned myocardium
A recent controversy has centered around the hypothesis that proteolytic degradation products of cTnI may play a role in the pathogenesis of stunned and/or hibernating myocardium (for a review see Marston and Redwood30). In rodent species, cTnI has a half-life of approximately 3 days.114 Like other contractile proteins, cTnI is constantly being synthesized and degraded in the heart. Degradation of troponin subunits (and their release into the circulation) increases in response to cardiac injury.
Troponin mutations and familial cardiomyopathy
FHC is an autosomal dominant disorder with a heterogeneous presentation including left ventricular hypertrophy, myofibrillar and myocyte disarray, and sudden cardiac death (for a review see Maron129 and Roberts and Ulrich130). FHC is estimated to have a prevalence of about 0.2% in young adults and is the most common cause of sudden death in adolescents and young adults.131 FHC is caused by mutations in genes encoding sarcomeric proteins including β-MyHC, myosin light chains 1 and 2,
Acknowledgements
This work was supported in part by NIH grant R37HL22231 and PO1 62426 to R.J.S. and a grant from the Commonwealth of Pennsylvania to M.S.P. We thank Lisa Gottschalk for expert preparation of the figures.
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