BPS2026 – Computational assessment of the regulation of excitation-contraction coupling by FKBP12.6

Previous studies demonstrate a strong affinity between FKBP12.6 and the cardiac ryanodine receptor (RyR2). Experimental studies demonstrate that changes in FKBP12.6 can alter the calcium transient. FKBP12.6 is upregulated in diseases such as heart failure. However, some studies suggest that, despite this strong affinity, only a minority (10% to 20%) of RyR2 channels are actually bound by FKBP12.6. This project explores the functional significance of FKBP12.6 in cardiac myocytes. Employing a Monte Carlo Markov chain (MCMC) computational model of excitation-contraction coupling in the rat ventricular myocyte, this project elucidates the sensitivity of calcium signaling in cardiac physiology, demonstrating how small proportions (10% to 20%) can precipitate substantial physiological responses. Systematic simulations were conducted using the ECC computational model, varying the average allosteric connectivity (Ej) and the change in free energy experienced by RyR2 channels upon allosteric coupling interactions between either open (Eoo) or closed (Ecc) states. Results revealed that increasing coupling among closed channels by 25% alone is sufficient to fully inhibit calcium ion release into the subspace. These findings underscore the delicate sensitivity of cardiac biophysiology, wherein changes within the 10%–25% range can yield extensive downstream effects. Consequently, the present study affirms that even the limited yet potent presence of FKBP12.6 associated with RyR2 merits significant consideration in this ongoing discourse.