Cardiac contractility: how calcium activates the myofilaments.
In both cardiac and skeletal muscle, the force-generating molecular motors (crossbridges) are turned on by increasing the intracellular free calcium level that regulates the troponin-tropomyosin system. However, calcium activation is a two-way process in the sense that activated crossbridges also affect the troponin-tropomyosin system. Here we review the mechanism of calcium action on myofilament proteins, particularly tropomyosin, that affects both the extent and the rate of force development and hence the contractility of the myocardium. At low myoplasmic Ca2+ concentrations tropomyosin is located at the edge of the thin filament, thereby interfering with the formation of strong actin-myosin linkages (blocked state). An increase in Ca2+ activity causes an azimuthal shift of tropomyosin around the filament (by about 30 degrees), thereby increasing the probability of low-force crossbridge interaction, a process which by cooperative effects induces further tropomyosin movement (by an additional 10 degrees) which results in the open state of the filament characterized by forceful crossbridge interaction. (This mechanism may be analogous to that in ligand-gated ion channels, where ligand binding increases the open probability of the pore.) The extent of activation then depends on the free Ca2+ concentration and on the calcium sensitivity of the thin filament that may be affected by protein phosphorylation, crossbridge attachment, the troponin isoform composition of the filament, and novel calcium-sensitizing drugs that act on the contractile or regulatory proteins and thus increase the force of the heart.
Rüegg
J C
JC
Physiologisches Institut, Universität, Heidelberg, Germany.
D008841:Actin Cytoskeleton / Q000502:physiology*; D000199:Actins / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000502:physiology*; D006801:Humans; D008955:Models, Cardiovascular; D009200:Myocardial Contraction / Q000502:physiology*; D009218:Myosins / Q000378:metabolism; D014335:Tropomyosin / Q000378:metabolism; D019209:Troponin C / Q000378:metabolism
D000199:Actins; D014335:Tropomyosin; D019209:Troponin C; D009218:Myosins; D002118:Calcium