Kinetic schemes for luminal-triggered Ca²⁺ feedthrough. Ca²⁺ activation (scheme 1, A- and L- sites) and Ca²⁺ inactivation (scheme 3, I₁ and I₂-sites). Each pair of open and closed states is associated with different functional states of individual RYR2 subunits, and the numbers refer to the entries in Table IV describing these stoichiometries. Asterisks indicate changes in subunit stoichiometry, and these depend on binding of Ca²⁺ or Mg²⁺. Also shown are their corresponding simplified schemes (schemes 2 and 4) and the overall scheme (scheme 5) resulting from the combined action of activation and inactivation. The reaction rates in scheme 5 have complex dependencies on [Ca²⁺] and [Mg²⁺], and these are derived in Eqs. 2–13. Reaction rates that depend on the Ca²⁺ and Mg²⁺ concentrations at the cytoplasmic pore mouth will depend on the permeability of these ions in the channel (Eqs. 1–4). Hence, they are given subscripts “o” and “c” to indicate the different rates associated with open and closed channels, respectively. In scheme 5, the open and closed status of the channel associated with each kinetic state is indicated by the subscripts “O” and “C,” respectively.