Aims: 

The main goal of the study was to propose a simple, biophysically reasonable electron-conformational theory for the ryanodine receptor channel (RyR) and, on that basis, present a stochastic model to describe RyR cluster and Ca²⁺ release unit (RU) in cardiomyocytes.

Methods: 

In addition to a fast electronic degree of freedom, the RyR channel is characterized by a slow classical conformational coordinate, Q, obeying Langevin dynamics, which specifies the RyR channel calcium conductance. The RyR gating is specified by conformational dynamics, Ca²⁺ induced direct electronic transitions, quantum tunnelling and thermal transitions. To account for the RyR cooperativity effects we have introduced the RyR-RyR conformational coupling.

Results: 

We have reproduced all the features of single RyR gating both under stationary conditions and Ca²⁺ stimulus, including the activation-inactivation phenomenon. Calcium RU modelled by the 11 × 11 RyR cluster revealed different regimes depending on the sarcoplasmic reticulum (SR) Ca²⁺ loads and lumenal Ca²⁺ refilling rate. The optimal mode of RU functioning during Ca²⁺ -induced calcium release implies a fractional release with a robust termination due to a decrease in SR Ca²⁺ load. SR overload leads to instabilities with strong spontaneous low-frequency modulations of Ca²⁺ release and clear tendency to auto-oscillation regime with spontaneous RyR channel opening and closure.

Conclusion: 

Electron-conformational model can successfully describe all the features of RyR gating and RU functioning. The model may be used to construct the appropriate discrete-state Markov scheme with physically clear picture of the underlying mechanisms of transitions and algorithms to estimate the appropriate probabilities.

Supported by The Wellcome Trust, RFBR Grants Nos.05-04-48352, 07-04-96126..