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Solaro RJ. Regulation of Cardiac Contractility. San Rafael (CA): Morgan & Claypool Life Sciences; 2011.

Cover of Regulation of Cardiac Contractility

Regulation of Cardiac Contractility.

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Left Ventricular Diastolic and Systolic Pressure, Ejection, and Relaxation Reflect Sarcomeric Mechanical Properties

The fundamental structural unit of the cardiac muscle cell responsible for force and shortening capability is the sarcomere (Reviewed in Kobayashi and Solaro, 2005). Figure 6 illustrates the molecular makeup of the region of over lap between thin and thick filaments. The reaction of the myosin cross-bridges, which are molecular motors housed in the sarcomeric thick filaments, with the actins of the thin filaments generates active cellular force, shortening, and power. In Figure 6 the cross-bridge is demonstrated during diastole, when reaction with actin is blocked by tropomyosin (Tm) and during systole, when cross-bridges are at the end of a power stroke after reacting with actin and splitting ATP. The reaction cycle of the cross-bridge with actin begins with attachment followed by a movement of the lever arm of the myosin head, which impels the thin filament in each half-sarcomere to slide toward the center. The cycle ends with detachment (reviewed in Hinken and Solaro, 2007). MgATP hydrolysis powers the force generation and shortening and provides the energy for these movements and it is generally agreed that one ATP is split per cycle. In entering the diastolic state ATP binds very rapidly cross-bridge and is rapidly split into ADP and Pi, which remains bound. In this state the cross-bridge is highly reactive with actin, but the actins are not available owing to a steric block imposed by the position of Tm on the thin filament. As shown in Figure 6 binding of Ca to TnC promotes the movement of Tm, making actin sites available. The cross-bridge can now attach and engage a catalytical cycle in which there are step-wise releases of Pi and ADP, and isomerization of the cross-bridge that is geared into a progressive change in mechanical state of the cross-bridge leading to thin filament sliding. With the release of ADP and Pi, the cross-bridges complete the power stroke and transfer into a nucleotide-free rigor state, which is strongly bound. Detachment requires binding of MgATP and the cycle may begin again depending on actins availability.

Figure 6. Molecular mechanisms of sarcomere activation.

Figure 6

Molecular mechanisms of sarcomere activation. The left panel shows the diastolic state of a region of overlap of thin and thick filaments illustrating detailed structure and location of major protein strands consisting of actin and tropomyosin (Tm). Attached (more...)

Figure 6 also illustrates the complex protein-protein interactions triggered by Ca2+ binding to the thin filament. TnC is one component of troponin (Tn) a hetero-trimeric protein complex consisting also of TnI, named for its prominent inhibitory activity, and TnT, named for its Tm binding activity. As shown in the left panel of Figure 6, in diastole, both Tn and Tm are situated on the thin filament in positions that block actin sites or hinder the actin-cross-bridge reaction. Tm is immobilized in the blocking position by cTnI, which is tethered to actin, and by the tail of TnT, which comes from the Tn complex in register on the opposite actin strand. The binding of cTnI to actin occurs via two regions, a highly basic inhibitory peptide and a second actin binding region. These regions flank a switch peptide, which binds to cTnC when Ca2+ binds to the N-lobe of cTnC, which houses a single regulatory Ca2+ -binding site, thereby participating in the mechanism by which Tn releases the thin filament from inhibition. An important domain of TnI is a unique N-terminal peptide, which has phosphorylation sites for PKA. In the absence of phosphorylation, the peptide reacts with TnC and enhances the Ca-affinity of TnC. With phosphorylation, the peptide no longer interacts with TnC and there is a suppression of the affinity of TnC for Ca2+.

The reaction of the switch peptide with the N-lobe of TnC is promoted by Ca-binding and exposure of a hydrophobic patch on TnC. The result is an induction of release of TnI from its inhibitory position. In association with this release of TnI, there are movements of TnT as the Tn complex pivots on the thin filament releasing Tm, which is now mobile. Actin sites for reaction with cross-bridges are exposed and the force and shortening producing cross-bridge cycle proceeds. There is also evidence that the reaction of cross-bridges with the thin filament can promote more actin-cross-bridge reactions by cooperative, feedback mechanisms. The strongly reacting cross-bridge has been demonstrated to increase the affinity of TnC for Ca2+ as well as to move Tm further away from the region of actin that reacts with the cross-bridges.

Interactions of regulatory proteins with thick filament myosin also affect the ability of cross-bridges to react with the thin filament, especially the kinetics of the cross-bridge cycle. The major mechanisms involve influences of the regulatory myosin light chain (MLC2) and myosin binding protein C (MyBP-C), both of which are illustrated in Figure 5 as interacting with the lever arm region of the cross-bridge. These proteins affect the radial disposition of the cross-bridge i.e. its movement relative to the main thick filament backbone. For example removal of MyBP-C by genetic approaches or phosphorylation by PKA causes the cross-bridge to move in a radial direction away from the backbone of the thick filament. Phosphorylation of MLC2 by a Ca-calmodulin dependent kinase (MLCK) also induces this radial movement. Other important determinants of the number of cross-bridges reacting with the thin filaments are the sarcomere length, and the load (velocity of shortening).

Elements in the sarcomeres are important determinants of passive elastic properties of the cell and thus diastolic properties of the ventricular chambers (Krueger and Linke, 2011). They also appear to affect signaling cascades, systole and contractility. A major molecular spring is the giant protein, titin. Interactions of titin with proteins of the sarcomere are illustrated in Figures 5 and 6. Titin extends from the mid-line of the sarcomere to the Z-disk. The region near the Z-line houses a stretch of amino acids that are coiled and act as a spring. As the sarcomere is passively stretched in diastole by the VR, titin elongates giving rise to passive tension. The spring like action of titin may be important also as the sarcomeres shorten and generate a restoring force producing a sucking action that is likely to be important in early diastole. Moreover, regions of titin in the overlap region of the sarcomere interact with myosin binding protein C. This interaction may affect the radial movement of the cross-bridges described above. These findings have led to new concepts regarding how diastolic state i.e. the stretch on titin, may affect systolic state and thus contractility. Thus, the conformational changes in titin with the stretch during diastole may also affect cross-bridge disposition. Although not discussed here, there is emerging evidence that the stress-strain relation of titin is not a constant but a variable controlled by phosphorylation. Although not depicted in detail in the figures, the Z-disc of the sarcomere not only anchors the thin filaments, but also links sarcomeres in series by titin and thin filaments interactions. There are also lateral connections linking the sarcomere to the surface membrane. In addition to its role in force transmission, the Z-disc is emerging as a significant locus of communication within the cells.

Copyright © 2011 by Morgan & Claypool Life Sciences.
Bookshelf ID: NBK54086


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