Regulation of Contraction in Striated Muscle

Departments of Physiology and Biophysics and of Bioengineering, University of Washington, Seattle, Washington; and Department of Physiology, University of California at Los Angeles, Los Angeles, California Gordon, A. M., E. Homsher, and M. Regnier. Regulation of Contraction in Striated Muscle. Physiol. Rev. 80: 853-924, 2000. Ca 2+ regulation of contraction in vertebrate striated muscle is exerted primarily through effects on the thin filament, which regulate strong cross-bridge binding to actin. Structural and biochemical studies suggest that the position of tropomyosin (Tm) and troponin (Tn) on the thin filament determines the interaction of myosin with the binding sites on actin. These binding sites can be characterized as blocked (unable to bind to cross bridges), closed (able to weakly bind cross bridges), or open (able to bind cross bridges so that they subsequently isomerize to become strongly bound and release ATP hydrolysis products). Flexibility of the Tm may allow variability in actin (A) affinity for myosin along the thin filament other than through a single 7 actin:1 tropomyosin:1 troponin (A 7 TmTn) regulatory unit. Tm position on the actin filament is regulated by the occupancy of NH-terminal Ca 2+ binding sites on TnC, conformational changes resulting from Ca 2+ binding, and changes in the interactions among Tn, Tm, and actin and as well as by strong S1 binding to actin. Ca 2+ binding to TnC enhances TnC-TnI interaction, weakens TnI attachment to its binding sites on 1-2 actins of the regulatory unit, increases Tm movement over the actin surface, and exposes myosin-binding sites on actin previously blocked by Tm. Adjacent Tm are coupled in their overlap regions where Tm movement is also controlled by interactions with TnT. TnT also interacts with TnC-TnI in a Ca 2+ -dependent manner. All these interactions may vary with the different protein isoforms. The movement of Tm over the actin surface increases the "open" probability of myosin binding sites on actins so that some are in the open configuration available for myosin binding and cross-bridge isomerization to strong binding, force-producing states. In skeletal muscle, strong binding of cycling cross bridges promotes additional Tm movement. This movement effectively stabilizes Tm in the open position and allows cooperative activation of additional actins in that and possibly neighboring A 7 TmTn regulatory units. The structural and biochemical findings support the physiological observatio