Structure-Function Relationship of the Ryanodine Receptor Cluster Network in Sinoatrial Node Cells

Area of Science:

• Cardiovascular Physiology
• Cellular Electrophysiology
• Calcium Signaling

Background:

• Sinoatrial node cell (SANC) action potential rate is regulated by local calcium release (LCR) via ryanodine receptors (RyRs).
• LCR events propagate through a network of RyR clusters (CRUs) via calcium-induced calcium release (CICR), influenced by CRU size and location.

Purpose of the Study:

• To investigate the 3D structure of CRU networks in rabbit SANC using super-resolution microscopy.
• To develop a numerical SANC model incorporating experimental CRU data to explore functional properties.
• To determine how CRU size and location heterogeneities affect CICR and SANC firing rate.

Main Methods:

• Super-resolution structured illumination microscopy to image CRU networks in 3D.
• Development of a novel numerical SANC model based on experimental data.
• Computational simulations to analyze the impact of CRU heterogeneities on CICR and AP firing rate.

Main Results:

• Peripheral CRUs form a spatial mesh; two distinct CRU subpopulations identified with specific size distributions.
• Neighboring CRUs exhibit repulsive behavior; model simulations show CRU heterogeneities facilitate CICR and increase AP firing rate.
• Heterogeneities enhance absolute AP firing rates during β-adrenergic stimulation but reduce relative changes.

Conclusions:

• CRU size and location heterogeneities cooperatively optimize SANC function by facilitating CICR.
• This optimization is vital for cardiac pacemaker operation across physiological conditions.
• Dysfunction in CRU network optimization may contribute to age-related decline in heart rate reserve and disease.