Composite gating scheme proposed for hRyR2 activation by [Ca²⁺]_cyt represented as part of a larger mechanistic network. The red boxes represent the discretely resolved states in the model, with solid black arrows showing the transitions between the states. At very low [Ca²⁺]_cyt, the unliganded open state O_UL and an intermediate Ca²⁺-bound preopening closed state C_I are also resolved (shown in light blue boxes). Solid gray arrows represent the transitions to and from these states. The states and the transitions represented by gray boxes and light gray dotted arrows are not discretely resolved from single-channel data analysis. These extrapolations show how the linear kinetic schemes (Fig. 4 B) could form a subset of a larger network (which could be interpreted as a phenomenological MWC-type model). Transitions to flicker closed states C_F could occur from any of the Ca²⁺-bound open states, and those that are not resolved directly from the data are represented by gray boxes and light gray dotted arrows.