The 3-state model of muscle regulation revisited: is a fourth state involved?

The 3-state model of muscle regulation has been useful in explaining the roles of Ca2+ and myosin heads in activation and relaxation of striated muscle contraction. However, there are some phenomena, which cannot simply be explained by the 3-state model. These include increased Ca2+-binding caused by strong-binding myosin heads and residual active force at low Ca2+ in the case of familial hypertrophic cardiomyopathy. Here, I review experimental data which provide evidence for an additional state, a myosin-induced Open state present in the absence of Ca2+ (Open-Ca2+) which like the normal Open+Ca2+ state, is an active state and can allow myosin heads to cycle and generate force. A schematic diagram is presented which shows that the formation of the Open-Ca2+ state is on a parallel path with the formation of the Open+Ca2+ state and can contribute to activation.