During activation at higher heart rates the formation of the cTnC·3Ca2+ complex will play the
FG4592 role, leading to a rapid thin filament activation and force development. Relaxation begins with the dissociation of Ca2+ from site II, thus increasing the population of cTnC·2Ca2+. However, there is now agreement that the rate of relaxation is determined by processes intrinsic to the cardiac sarcomere rather than by the rate of Ca2+ removal from site II [24], [25] and [26]. The mechanisms responsible for the fast relaxation kinetics are still being investigated and probably involve several different steps in the crossbridge cycle. Among the factors implicated in rapid relaxation are lengthening-induced strain on cross-bridges, leading to their more rapid detachment from actin, and phosphate-induced reversal of the crossbridge power stroke [26]. Also, evidence has been presented indicating that increase in
heart rate is associated with augmented levels of myofilament protein phosphorylation and reduced myofilament Ca2+ sensitivity [27]. We suggest that the C-domain of cTnC may influence relaxation rate as a consequence of the formation of cTnC·2Ca2+ early in the relaxation phase. By reducing thin filament activation, the Ca2+ bound to sites III and IV, acting in conjunction with factors listed above, might promote a faster rate of relaxation. As suggested previously [2], variation in the Ca2+/Mg2+ binding ratio at sites III and IV has the potential to provide an on-going measure of the frequency and intensity of Ca2+ activation in cardiac muscle. To determine whether the Ca2+/Mg2+ sites do indeed serve such a function will require a more extensive investigation of the kinetic and structural correlates of C-terminal cation binding.
