Stochastic Modeling of Calcium Release Units Reveals a Strong Dependence of Calcium Release Variability on Cluster Size

Gustavo Montes Novaes1, Enrique Alvarez Lacalle2, Sergio Alonso3, Rodrigo Weber dos Santos4
1Centro Federal de Educação Tecnológica de Minas Gerais - CEFET-MG, 2Associate Professor UPC BarcelonaTech, 3Universitat Politècnica de Catalunya, 4Federal University of Juiz de Fora


Abstract

Intracellular calcium (Ca²⁺) dynamics drive contractile function in cardiac myocytes. In particular, L-type Calcium Channels (LCCs) and Ryanodine Receptors (RyRs) are organized in microdomains, where LCCs trigger substantial Ca²⁺ release from the Sarcoplasmic Reticulum (SR) via RyRs. We present a minimal Calcium Release Unit (CRU) model for human ventricular myocytes that integrates a recently developed Markov Chain (MC)-based description of LCCs, replacing classical Hodgkin-Huxley gates. Our approach builds on previously published MC-based frameworks for the human heart, enabling stochastic gating and faithfully reproducing both spontaneous and evoked local Ca²⁺ release events. Despite its simplicity, our single-CRU system captures key features of microscale and macroscale Ca²⁺ cycling, revealing how the variability in Ca²⁺ release depends on microdomain size. In particular, simulations show a sharp transition in Ca²⁺ release dynamics around cluster sizes of ~100 LCC channels, marking a critical threshold where stochastic behavior gives way to deterministic-like dynamics.