BPS2026 – Amplification of stochastic resonance in cardiac pacemaker cells via coupling of intracellular calcium signals to membrane voltage

Stochastic resonance is an important phenomenon for signal detection and processing in excitable cells. Cardiac pacemaker cells operate via an intracellular calcium oscillator coupled to a surface membrane oscillator, known as the coupled-clock, or coupled-oscillator, system. We have recently shown that stochastic resonance is involved in generating robust action potential (AP) firing when signal heterogeneity and noise within the coupled-oscillator system increase at low firing rates close to sinus arrest. Here, we investigated in more detail how stochastic resonance functions within the coupled-oscillator system. Membrane voltage (perforated patch clamp) and intracellular calcium (high-speed camera) were measured simultaneously in single sinoatrial node cells isolated from rabbit hearts. We applied white noise through the patch pipette to awaken non-firing (dormant) cells. Cross-correlation analysis revealed that, even before the first action potential (AP) fired, membrane potential and calcium signals became more synchronized during noise application. We further tested whether the calcium oscillator was indeed involved in this synchronization process by applying cyclopiazonic acid (CPA) to block SERCA, the sarcoplasmic reticulum calcium pump. Under CPA, the cell was less capable of achieving stochastic resonance, indicated by infrequent APs during noise application. Looking deeper into the calcium oscillator, we also examined its local calcium releases (LCRs). Under noise, LCRs significantly increased in size and facilitated AP firing. These results were reproduced in a cellular numerical model. Thus, stochastic resonance is not a purely electrical phenomenon: L-type calcium current, ryanodine receptor-assisted calcium release, and sodium-calcium exchanger create explosive positive feedback in the coupled-oscillator system which substantially enhances cell sensitivity to stochastic resonance. We interpreted our results in the context of the AP ignition concept and disorder-order transition. Although counterintuitive, a noisy, disordered environment can trigger system self-organization and order.