Fig. 8.

Model summarizing the relationship between the phosphorylation level of RyR2 and channel gating behavior. Large vertical arrow on the left indicates increasing P _o, and large horizontal arrow indicates increasing RyR2 phosphorylation levels. At the basal levels of phosphorylation, channel P _o is maintained at a low level and the channel gates in a Ca²⁺-sensitive manner, fully responsive to the levels of other channel regulators. Lowering the free [Ca²⁺] to subactivating levels (<1 nM) reduces P _o to zero. The fully dephosphorylated channel (dephosphorylated state) gates with a higher P _o than the channel phosphorylated at basal levels but remains sensitive to cytosolic Ca²⁺ (again, lowering the free [Ca²⁺] to subactivating levels [<1 nM] reduces P _o to zero). When the channel is maximally phosphorylated (hyperphosphorylated state), exceptionally long open states result, leading to high P _o values. In this conformation, RyR2 is uncoupled from the usual regulatory effects of cytosolic Ca²⁺ and cannot be closed by lowering cytosolic [Ca²⁺] below activating levels. P and de-P indicate phosphorylation and dephosphorylation, respectively