Figure 12.

Cartoon representation of the putative channel conformations in the gating model for hRyR2. The diagrams are not meant to depict the actual structure of the channel or of the ligand-binding sites and are purely schematic in nature. The nonresponsive closed state (C_NR; gray) is represented with binding sites that are not receptive to the ligand, although it should be noted that this conformation cannot activate to the unliganded open (green) state either. This can only happen from the responsive closed state (C_R; purple), which is able to bind the ligand (Ca²⁺; shown as orange circles) and undergo a conformational change to ligand-bound open states (yellow). The channel can also move into intermediate closed conformations where its putative ligand-dependent gate toward the cytoplasmic side (cyt) is shut while Ca²⁺ is bound as shown (pink). This was resolved at very low [Ca²⁺]_cyt as C_I in our kinetic schemes. Flicker closing events (C_F; light blue) can occur for the Ca²⁺-bound open states where the channel is nonconducting probably because of the collapse of its selectivity filter near the luminal face of the channel (lum). Orange arrows denote the open (conducting) states of the channel where the putative gates at the selectivity filter region and at the helix–bundle crossover are open simultaneously.