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 l evel that regulates the troponin-tropomyosin system. However, calcium activ ation is a two-way process in the sense that activated crossbridges also af fect the troponin-tropomyosin system. Here we review the mechanism of calci um action on myofilament proteins, particularly tropomyosin, that affects b oth the extent and the rate of force development and hence the contractilit y of the myocardium. At low myoplasmic Ca2+ concentrations tropomyosin is l ocated at the edge of the thin filament, thereby interfering with the forma tion of strong actin-myosin linkages (blocked state). An increase in Ca2+ a ctivity causes an azimuthal shift of tropomyosin around the filament (by ab out 30 degrees), thereby increasing the probability of low-force crossbridg e interaction, a process which by cooperative effects induces further tropo myosin movement (by an additional 10 degrees) which results in the open sta te of the filament characterized by forceful crossbridge interaction. (This mechanism may be analogous to that in ligand-gated ion channels, where lig and binding increases the open probability of the pore.) The extent of acti vation then depends on the free Ca2+ concentration and on the calcium sensi tivity 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 regulat ory proteins and thus increase the force of the heart.