Allosteric interactions between RyR channels justify intracellular Ca2+ release of skeletal muscle in quantitative detail

This modeling study explains the intracellular Ca2+ release that controls contraction of skeletal muscles of mammals as emerging from a statistical ensemble of couplons. Couplons are constituted by identical sarcoplasmic reticulum RyR1 channels, arranged in native "checkerboard" double-row pattern, with alternate channels (the V class) in physical contact with CaV1.1 tetrads resident in the electrically excitable T-tubular membrane. Activation starts from these and propagates allosterically to the RyRs devoid of CaV contacts (the C class). Both activations are imposed by changes in free energy of channel states, derived from electrical work on the CaV mobile charges. The allosteric connections, resulting in reciprocal energy changes, are interlaced, so that the couplon becomes a highly reactive continuum where allosteric effects may propagate from end to end. A robust inactivation of C channels maintains this highly excitable device under graded voltage control. The model reproduces within the variance of experimental observations the cell level records of Ca2+ flux, including voltage dependence and kinetics, under multiple combinations of voltage clamp pulses, and accounts for the conditioning effects known as "quantal release" and "deterministic inactivation." The simulations, which describe individual channel evolutions as stochastic Markov chains, are also consistent with the Ca2+ events recorded at the subcellular microdomain level as well as observations of coupled gating in bilayers. No explicit Ca2+ roles on activation or inactivation are required. The good model-vs.-experiment match enables inferences on mechanisms, their specializations in muscle tissues, and their variations in different taxa. It also encourages modular incorporation into more comprehensive models of cellular function.