Electron-conformational model of ryanodine receptor lattice dynamics

Area of Science:

• Biophysics
• Computational Biology
• Molecular Modeling

Background:

• The ryanodine receptor (RyR) is a critical calcium channel involved in cellular signaling.
• Understanding RyR lattice dynamics is essential for comprehending calcium-induced calcium release (CICR).
• Existing models may not fully capture the complex interplay of electronic and conformational states in RyRs.

Purpose of the Study:

• To propose a novel, physically grounded electron-conformational model for the ryanodine receptor (RyR).
• To theorize RyR lattice responses to L-type channel triggering as an induced non-equilibrium phase transition.
• To elucidate the mechanisms underlying calcium spark generation and RyR lattice auto-oscillations.

Main Methods:

• Modeling each RyR with single open/closed electronic states using a pseudospin approach.
• Incorporating a slow classical conformational coordinate (Q) for calcium conductance.
• Assuming inter-channel conformational coupling determines RyR lattice cooperativity.

Main Results:

• RyR lattice firing via nucleation and domino-like opening at threshold sarcoplasmic reticulum (SR) calcium load.
• Generation of sufficient calcium release for calcium sparks.
• Demonstration of robust termination of fractional release via decreased SR calcium load.
• Observation of RyR lattice auto-oscillations under SR calcium overload.

Conclusions:

• The proposed electron-conformational model provides a unified framework for RyR lattice behavior.
• RyR lattice function during CICR involves fractional release and termination by conformational strain.
• SR calcium overload can induce auto-oscillations in the RyR lattice, impacting cellular calcium dynamics.