The scheme involves multiple, weak and cooperative interactions between the two sets of Ca2+ binding sites on troponin and between these sites and actin, troponin T, and troponin I. In relaxed muscle, myosin cannot bind to actin because of strong inhibitory interactions of troponin and tropomyosin on the thin filament. These inhibitory interactions are relieved when Ca2+ binds to the regulatory site on troponin, leading to a conformational change in the troponin-tropomyosin complex. This movement enables myosin to bind to actin and form the cross-bridges that are responsible for force generation.
The number of cross-bridges formed depends on the Ca2+ concentration and the degree of cooperative binding of Ca2+ to troponin. At low Ca2+ concentrations, the number of cross-bridges formed is limited by the availability of Ca2+ binding sites on troponin. As the Ca2+ concentration increases, more Ca2+ ions bind to troponin and the number of cross-bridges formed increases. However, at high Ca2+ concentrations, the cooperative binding of Ca2+ to troponin decreases and the number of cross-bridges formed also decreases.
The decrease in the number of cross-bridges formed at high Ca2+ concentrations is due to the fact that the cooperative binding of Ca2+ to troponin leads to a conformational change in the troponin-tropomyosin complex that results in a decreased affinity of myosin for actin. This decreased affinity is thought to be due to the fact that the conformational change in troponin-tropomyosin complex moves the tropomyosin strand closer to the actin filament, which sterically hinders the binding of myosin to actin.
Thus, the relationship between force and Ca2+ sensitivity in skeletal muscle is a complex one that is determined by the cooperative binding of Ca2+ to troponin and the subsequent conformational changes in the troponin-tropomyosin complex.